Isoquinolin-3-yl carboxamides and preparation and use thereof

ABSTRACT

Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an isoquinoline compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer&#39;s disease, lung disease, inflammation, auto-immune diseases and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/328,210, filed Apr. 27, 2016, which is incorporated herein byreference in its entirety.

BACKGROUND Technical Field

This disclosure relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an isoquinoline compound or salts or analogs thereof, in thetreatment of disorders characterized by the activation of Wnt pathwaysignaling (e.g., cancer, abnormal cellular proliferation, angiogenesis,Alzheimer's disease, lung disease, inflammation, auto-immune diseasesfibrotic disorders, cartilage (chondral) defects, and osteoarthritis),the modulation of cellular events mediated by Wnt pathway signaling, aswell as genetic diseases and neurological conditions/disorders/diseasesdue to mutations or dysregulation of the Wnt pathway and/or of one ormore of Wnt signaling components. Also provided are methods for treatingWnt-related disease states, as well as neurologicalconditions/disorders/diseases linked to overexpression of DYRK1A.

Background

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 19 genes identified in the human. Members of theWnt family of signaling molecules mediate many short- and long-rangepatterning processes during invertebrate and vertebrate development. TheWnt signaling pathway is known for its role in the inductiveinteractions that regulate growth and differentiation, and it also playsroles in the homeostatic maintenance of post-embryonic tissue integrity.Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression ofgenes including c-myc, c jun, fra-1, and cyclin D1. In addition,misregulation of Wnt signaling can cause developmental defects and isimplicated in the genesis of several human cancers. The Wnt pathway hasalso been implicated in the maintenance of stem or progenitor cells in agrowing list of adult tissues including skin, blood, gut, prostate,muscle, and the nervous system.

Dual specificity tyrosine-phosphorylation-regulated kinase 1A is anenzyme that in humans is encoded by the DYRK1A gene. DYRK1A is a memberof the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK)family. DYRK1A contains a nuclear targeting signal sequence, a proteinkinase domain, a leucine zipper motif, and a highly conservative13-consecutive-histidine repeat. It catalyzes its autophosphorylation onserine/threonine and tyrosine residues. It may play a significant rolein a signaling pathway regulating cell proliferation and may be involvedin brain development. DYRK1A is localized in the Down syndrome criticalregion of chromosome 21, and is considered to be a candidate gene forlearning defects associated with Down syndrome. DYRK1A is also expressedin adult brain neurons, indicating that DYRK1A may play a role in themature central nervous system. Thus, several lines of evidence point tosome synaptic functions of DYRK1A. For instance, it has been found thatDYRK1A phosphorylates and modulates the interaction of severalcomponents of the endocytic protein complex machinery (Dynamin 1,Amphiphysin, and Synaptojanin), suggesting a role in synaptic vesiclerecycling. In addition, a polymorphism (SNP) in DYRK1A was found to beassociated with HIV-1 replication in monocyte-derived macrophages, aswell as with progression to AIDS in two independent cohorts ofHIV-1-infected individuals.

SUMMARY

The present disclosure provides methods and reagents, involvingcontacting a cell with an agent, such as an isoquinoline compound, in asufficient amount to antagonize a Wnt activity, e.g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

The present disclosure also provides methods and reagents, involvingcontacting a cell with an agent, such as an isoquinoline compound, in asufficient amount to antagonize DYRK1A activity, e.g., i) to normalizeprenatal and early postnatal brain development; ii) to improve cognitivefunction in youth and adulthood; and/or iii) to attenuateAlzheimer's-type neurodegeneration.

Some embodiments disclosed herein include Wnt and/or DYRK1A inhibitorscontaining an isoquinoline core. Other embodiments disclosed hereininclude pharmaceutical compositions and methods of treatment using thesecompounds.

One embodiment disclosed herein includes a compound having the structureof Formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R⁴⁵;

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), and —CF(C₁₋₉ alkyl)₂; wherein each alkyl of—CF(C₁₋₉ alkyl)₂ is, independently, optionally substituted with one ormore halides; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁸ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁵ is independently selected from the group consisting of H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, two adjacent R⁴⁵ taken together form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R⁴⁶ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁷ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

each p is independently 0 or 1.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring; so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), and —CF(C₁₋₉ alkyl)₂; wherein each alkyl of—CF(C₁₋₉ alkyl)₂ is, independently, optionally substituted with one ormore halides; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

R⁷ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, one of R⁷ and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹⁵ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R¹⁸ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are taken together toform a heterocyclyl optionally substituted with 1-10 R⁴⁰;

R²¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

R²² and R²³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, R²² and R²³ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R²⁴, R²⁵, and R²⁶ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R²⁷, R²⁸, and R²⁹ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, R²⁷ and R²⁸ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³⁰ and R³¹ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, R³⁰ and R³¹ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³² and R³³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

R³⁴ and R³⁵ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

alternatively, R³⁴ and R³⁵ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁸ independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

R⁴⁶ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁷ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

each X is O or S; and

each p is independently 0 or 1.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R⁴⁵;

with the proviso that R³ is not

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), —N(R⁴⁸)(R⁴⁹), —CF(C₁₋₉ alkyl)₂, —(C₁₋₄alkylene)_(p)O(C₃₋₉ alkyl), and —(C₂₋₉ alkynyl) optionally substitutedwith one or more halides; wherein each alkyl of —CF(C₁₋₉ alkyl)₂ is,independently, optionally substituted with one or more halides; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

with the proviso that R⁶ is not unsubstituted —(CH₂)tetrahydropyranyl;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R⁴⁴, —C(═O)(R⁵⁰), —(C₁₋₄ alkylene)C(═O)OR⁵¹,—(C₁₋₄ alkylene)aryl optionally substituted with one or more halides,—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides, and —SO₂(R⁵²); wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

alternatively, two R³⁶ attached to the same carbon atom can togetherrepresent ═O to form a carbonyl group;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —N(R⁵³)₂, —C(═O)(R⁵⁰), —C(═O)OR⁵¹, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁸ independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁵ is independently selected from the group consisting of H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

alternatively, two adjacent R⁴⁵ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R⁴⁶ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁷ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁸ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R⁴⁹ is attached to the nitrogen and is selected from the groupconsisting of —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

R⁵⁰ is selected from the group consisting of H, unsubstituted —(C₃₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁵¹ is selected from the group consisting of H, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁵² is selected from the group consisting of unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

each R⁵³ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), andunsubstituted —(C₂₋₅ alkynyl);

each p is independently 0 or 1; and

with the proviso that Formula I is not a structure selected from thegroup consisting of:

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring; so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), —N(R⁴⁸)(R⁴⁹), —CF(C₁₋₉ alkyl)₂, —(C₁₋₄alkylene)_(p)O(C₃₋₉ alkyl), and —(C₂₋₉ alkynyl) optionally substitutedwith one or more halides; wherein each alkyl of —CF(C₁₋₉ alkyl)₂ is,independently, optionally substituted with one or more halides; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

with the proviso that R⁶ is not unsubstituted —(CH₂)tetrahydropyranyl;

R⁷ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, one of R⁷ and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹⁵ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R¹⁸ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are taken together toform a heterocyclyl optionally substituted with 1-10 R⁴⁰;

R²¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R²² and R²³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, R²² and R²³ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R²⁴, R²⁵, and R²⁶ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

with the proviso that when R²⁵ is a single bond connecting R³ to theisoquinoline ring, R²⁴ and R²⁶ are not methyls;

alternatively, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R²⁷, R²⁸, and R²⁹ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, R²⁷ and R²⁸ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³⁰ and R³¹ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, R³⁰ and R³¹ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³² and R³³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

R³⁴ and R³⁵ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, R³⁴ and R³⁵ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁ 9 haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R⁴⁴, —C(═O)(R⁵⁰), —(C₁₋₄ alkylene)C(═O)OR⁵¹,—(C₁₋₄ alkylene)aryl optionally substituted with one or more halides,—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides, and —SO₂(R⁵²); wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

alternatively, two R³⁶ attached to the same carbon atom can togetherrepresent ═O to form a carbonyl group;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —N(R⁵³)₂, —C(═O)(R⁵⁰), —C(═O)OR⁵¹, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁸ independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

R⁴⁶ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁷ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁴⁸ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R⁴⁹ is attached to the nitrogen and is selected from the groupconsisting of —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

R⁵⁰ is selected from the group consisting of H, unsubstituted —(C₃₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁵¹ is selected from the group consisting of H, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁵² is selected from the group consisting of unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein;

each R⁵³ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), andunsubstituted —(C₂₋₅ alkynyl);

each X is O or S; and

each p is independently 0 or 1; and

with the proviso that Formula I is not a structure selected from thegroup consisting of:

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of Formula (I). Some embodiments includepharmaceutically acceptable salts of a compound of Formula (I).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a patient affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto Formula (I). Accordingly, the compounds and compositions providedherein can be used to treat cancer, to reduce or inhibit angiogenesis,to reduce or inhibit cellular proliferation and correct a geneticdisorder due to mutations in Wnt signaling components.

Other embodiments disclosed herein include methods of inhibiting DYRK1Aby administering to a patient affected by a disorder or disease in whichDYRK1A overexpression is implicated, such as Alzheimer's Disease,Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementiawith Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease,Pick's Disease, and additional diseases with pronouncedneurodegeneration such as Autism, Dementia, Epilepsy, Huntington'sDisease, Multiple Sclerosis; diseases and disorders associated withacquired brain injury such as Chronic Traumatic Encephalopathy,Traumatic Brain Injury, Tumor and Stroke.

Non-limiting examples of diseases which can be treated with thecompounds and compositions provided herein include a variety of cancers,diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis,ankylosing spondylitis, psoriasis, scleroderma, mycotic and viralinfections, osteochondrodysplasia, Alzheimer's disease, lung disease,bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to preparecompounds of Formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

Provided herein are compositions and methods for inhibiting one or moremembers of the Wnt pathway, including one or more Wnt proteins. OtherWnt inhibitors and methods for using the same are disclosed in U.S.application Ser. Nos. 13/614,296; 14/019,229; and Ser. No. 14/664,517,all of which are incorporated by reference in their entirety herein.

Provided herein are compositions and methods for inhibiting DYRK1A.Other DYRK1A inhibitors and methods for using the same are disclosed inU.S. application Ser. No. 14/664,517, which is incorporated by referencein its entirety herein.

Some embodiments provided herein relate to a method for treating adisease including, but not limited to, neurological diseases ordisorders, cancers, chronic inflammation, diabetic retinopathy,pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosingspondylitis, psoriasis, scleroderma, mycotic and viral infections, boneand cartilage diseases, lung disease, osteoarthritis, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli, bone density andvascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG),familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia, Müllerian-duct regression andvirilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilagediseases which can be treated with the compounds and compositionsprovided herein include bone spur (osteophytes), craniosynostosis,fibrodysplasia ossificans progressive, fibrous dysplasia, giant celltumor of bone, hip labral tear, meniscal tears, osteoarthritis,articular cartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), osteochondritis dissecans,osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis,and Salter-Harris fractures.

In some embodiments, non-limiting examples of a neurological disease ordisorder associated with tau protein, amyloid or alpha-synucleinpathology which can be treated with the compounds and compositionsprovided herein include, but are not limited to, Alzheimer's Disease,Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementiawith Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease,Pick's Disease, and additional diseases with pronouncedneurodegeneration such as Autism, Dementia, Epilepsy, Huntington'sDisease, Multiple Sclerosis; diseases and disorders associated withacquired brain injury such as Chronic Traumatic Encephalopathy,Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, non-limiting examples of diseases in which chronicinflammation is involved which can be treated with the compounds andcompositions provided herein include eye disorders, joint pain,arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast,lung, pancreas, and others), gastrointestinal disorders (ulcerativecolitis and inflammatory bowel diseases), pulmonary disorders (chronicobstructive pulmonary disorder and asthma), allergies, skin disorders(atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis,hepatitis, heart disease, myocarditis, stroke, lupus, and neurologicaldisorders such as multiple sclerosis, Parkinson's and dementia includingAlzheimer's disease.

In some embodiments, non-limiting examples of cancers which can betreated with the compounds and compositions provided herein includecolon, ovarian, pancreatic, breast, liver, prostate, and hematologiccancers.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by either the pathological activation or mutations of the Wntpathway or DYRK1A overexpression. The composition includes apharmaceutically acceptable carrier and a compound as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. In someembodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In variousembodiments, alkenyl groups can either be unsubstituted or substitutedwith one or more substituents. Typically, alkenyl groups will comprise 2to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbonatoms, or 2 carbon atoms).

As used herein, “alkynyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl,2-butynyl, and the like. In various embodiments, alkynyl groups caneither be unsubstituted or substituted with one or more substituents.Typically, alkynyl groups will comprise 2 to 9 carbon atoms (forexample, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chainchemical group containing only carbon and hydrogen, such as methylene,ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene,sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentyleneand neo-pentylene. Alkylene groups can either be unsubstituted orsubstituted with one or more substituents. In some embodiments, alkylenegroups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon double bond, such as ethenylene,1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene,2-butenylene, and the like. In various embodiments, alkenylene groupscan either be unsubstituted or substituted with one or moresubstituents. Typically, alkenylene groups will comprise 2 to 9 carbonatoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2carbon atoms).

As used herein, “alkynylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon triple bond, such as ethynylene,1-propynylene, 1-butynylene, 2-butynylene, and the like. In variousembodiments, alkynylene groups can either be unsubstituted orsubstituted with one or more substituents. Typically, alkynylene groupswill comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkoxy” means an alkyl-O— group in which the alkylgroup is as described herein. Exemplary alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy,hexoxy and heptoxy, and also the linear or branched positional isomersthereof.

As used herein, “haloalkoxy” means a haloalkyl-O— group in which thehaloalkyl group is as described herein. Exemplary haloalkoxy groupsinclude fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also thelinear or branched positional isomers thereof.

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that none of the rings in the ring system arearomatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. In some embodiments, carbocyclyl groupsinclude 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group withonly carbon atoms present in the ring backbone having 5 to 14 ringatoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14pi electrons shared in a cyclic array; wherein at least one ring in thesystem is aromatic. Aryl groups can either be unsubstituted orsubstituted with one or more substituents. Examples of aryl includephenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, andothers. In some embodiments, the aryl is phenyl.

As used herein, “arylalkylene” means an aryl-alkylene-group in which thearyl and alkylene moieties are as previously described. In someembodiments, arylalkylene groups contain a C₁₋₄alkylene moiety.Exemplary arylalkylene groups include benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclicarray; wherein at least one ring in the system is aromatic, and at leastone ring in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl,oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In someembodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl,pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, andpyrimidinyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, a halo is a chloro,bromo or fluoro. For example, a halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched, alkyl, alkenyl or alkynyl substituted with one ormore chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, ahaloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or1 carbon in length). The term “haloalkylene” means a diradical variantof haloalkyl, and such diradicals may act as spacers between radicals,other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls may besubstituted or unsubstituted with one or more substituents. In someembodiments, heterocycles have 3-11 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one to three of O, Nor S, and wherein when the heterocycle is five membered, it can have oneor two heteroatoms selected from O, N, or S. Examples of heterocyclylinclude azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.In some embodiments, the heterocyclyl is selected from azetidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single nonaromaticcyclic ring comprising at least one heteroatom in the ring systembackbone. Heterocyclyls may be substituted or unsubstituted with one ormore substituents. In some embodiments, heterocycles have 3-7 members.In six membered monocyclic heterocycles, the heteroatom(s) are selectedfrom one to three of O, N or S, and wherein when the heterocycle is fivemembered, it can have one or two heteroatoms selected from O, N, or S.Examples of heterocyclyls include azirinyl, aziridinyl, azetidinyl,oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl,thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl,thiomorpholinyl, and others.

As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone. Bicyclic heterocyclyls may be substituted or unsubstitutedwith one or more substituents. In some embodiments, bicyclicheterocycles have 4-11 members with the heteroatom(s) being selectedfrom one to five of O, N or S. Examples of bicyclic heterocyclylsinclude 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane,2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane,5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane,octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane,7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane,7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.

As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone and with the rings connected through just one atom. Spirocyclicheterocyclyls may be substituted or unsubstituted with one or moresubstituents. In some embodiments, spirocyclic heterocycles have 5-11members with the heteroatom(s) being selected from one to five of O, Nor S. Examples of spirocyclic heterocyclyls include2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane,2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane,6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane,2,5-diazaspiro[3.6]decane, and the like.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Substituents can include, for example,—(C₁₋₉ alkyl) optionally substituted with one or more of hydroxyl, —NH₂,—NH(C₁₋₃ alkyl), and —N(C₁₋₃ alkyl)₂; —(C₁₋₉ haloalkyl); a halide; ahydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [suchas —C(S)OR, —C(O)SR, and —C(S)R]; —(C₁₋₉ alkoxy) optionally substitutedwith one or more of halide, hydroxyl, —NH₂, —NH(C₁₋₃ alkyl), and —N(C₁₋₃alkyl)₂; —OPO(OH)₂; a phosphonate [such as —PO(OH)₂ and —PO(OR′)₂];—OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro;an azido; —SH; —S—R; —OSO₂(OR); a sulfonate [such as —SO₂(OH) and—SO₂(OR)]; —SO₂NR′R″; and —SO₂R; in which each occurrence of R, R′ andR″ are independently selected from H; —(C₁₋₉ alkyl); C₆₋₁₀ aryloptionally substituted with from 1-3R′″; 5-10 membered heteroaryl havingfrom 1-4 heteroatoms independently selected from N, O, and S andoptionally substituted with from 1-3 R′″; C₃₋₇ carbocyclyl optionallysubstituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from1-4 heteroatoms independently selected from N, O, and S and optionallysubstituted with from 1-3 R′″; wherein each R′″ is independentlyselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl). In some embodiments, the substituent isselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

The skilled artisan will recognize that some chemical structuresdescribed herein may be represented on paper by one or more otherresonance forms; or may exist in one or more other tautomeric forms,even when kinetically, the artisan recognizes that such tautomeric formsrepresent only a very small portion of a sample of such compound(s).Such compounds are clearly contemplated within the scope of thisdisclosure, though such resonance forms or tautomers are not explicitlyrepresented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g., mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The present disclosure includes all pharmaceutically acceptableisotopically labeled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include, but are not limited to,isotopes of hydrogen, such as ²H (deuterium) and ³H (tritium), carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as³⁵S.

The term “administration” or “administering” refers to a method ofproviding a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intralymphatic, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Themethod of administration can vary depending on various factors, e.g.,the components of the pharmaceutical composition, the site of thedisease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification or characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats, mice,rats, cows, sheep, pigs, goats, and non-human primates, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier”, “pharmaceuticallyacceptable diluent” or “pharmaceutically acceptable excipient” includesany and all solvents, co-solvents, complexing agents, dispersion media,coatings, isotonic and absorption delaying agents and the like which arenot biologically or otherwise undesirable. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. In addition, various adjuvants such as arecommonly used in the art may be included. These and other such compoundsare described in the literature, e.g., in the Merck Index, Merck &Company, Rahway, N.J. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 12th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Many such salts are known in the art, forexample, as described in WO 87/05297. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine.

“Patient” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate, or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound as provided herein isone which is sufficient to achieve the desired physiological effect andmay vary according to the nature and severity of the disease condition,and the potency of the compound. “Therapeutically effective amount” isalso intended to include one or more of the compounds of Formula I incombination with one or more other agents that are effective to treatthe diseases and/or conditions described herein. The combination ofcompounds can be a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. It will be appreciated that different concentrations may beemployed for prophylaxis than for treatment of an active disease. Thisamount can further depend upon the patient's height, weight, sex, ageand medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease.

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, ameliorating the underlying metabolic causes ofsymptoms, postponing or preventing the further development of adisorder, and/or reducing the severity of symptoms that will or areexpected to develop.

“Drug-eluting” and/or controlled release as used herein refers to anyand all mechanisms, e.g., diffusion, migration, permeation, and/ordesorption by which the drug(s) incorporated in the drug-elutingmaterial pass therefrom over time into the surrounding body tissue.

“Drug-eluting material” and/or controlled release material as usedherein refers to any natural, synthetic or semi-synthetic materialcapable of acquiring and retaining a desired shape or configuration andinto which one or more drugs can be incorporated and from whichincorporated drug(s) are capable of eluting over time.

“Elutable drug” as used herein refers to any drug or combination ofdrugs having the ability to pass over time from the drug-elutingmaterial in which it is incorporated into the surrounding areas of thebody.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and/or as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

The compounds and compositions described herein can be used to inhibitDYRK1A for treating a disorder or disease in which DYRK1A overexpressionis implicated, such as Alzheimer's Disease, Amyotrophic LateralSclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17(FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, andadditional diseases with pronounced neurodegeneration such as Autism,Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseasesand disorders associated with acquired brain injury such as ChronicTraumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

Some embodiments of the present disclosure include compounds of FormulaI:

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H, halide, unsubstituted —(C₁₋₃ haloalkyl), andunsubstituted —(C₁₋₃ alkyl);

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and halide.

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and F.

In some embodiments, R¹, R², R⁴, and R⁵ are all H.

In some embodiments, R¹ is F, and R², R⁴, and R⁵ are all H.

In some embodiments, R² is F, and R¹, R⁴, and R⁵ are all H.

In some embodiments, R⁴ is F, and R¹, R², and R⁵ are all H.

In some embodiments, R⁵ is F, and R¹, R², and R⁴ are all H.

In some embodiments, R³ is a 5-membered heteroaryl ring optionallysubstituted as defined anywhere herein.

In some embodiments, R³ is 5-membered heteroaryl ring optionallysubstituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵;

In some embodiments, there is the proviso that R³ is not

In some embodiments, R³ is selected from the group consisting of:furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,thiophenyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,pyrrolyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,

wherein each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring.

In some embodiments, R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 (e.g., 1-11,1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), and —CF(C₁₋₉ alkyl)₂; wherein each alkyl of—CF(C₁₋₉ alkyl)₂ is, independently, optionally substituted with one ormore halides; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), —N(R⁴⁸)(R⁴⁹), —CF(C₁₋₉ alkyl)₂, —(C₁₋₄alkylene)_(p)O(C₃₋₉ alkyl), and —(C₂₋₉ alkynyl) optionally substitutedwith one or more halides; wherein each alkyl of —CF(C₁₋₉ alkyl)₂ is,independently, optionally substituted with one or more halides; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein.

In some embodiments, there is the proviso that R⁶ is not unsubstituted—(CH₂)tetrahydropyranyl.

In some embodiments, R⁷ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein each —(C₁₋₄ alkylene)is, independently, optionally substituted with one or more substituentsas defined anywhere herein.

In some embodiments, R⁷ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, R⁸, R⁹, and R¹⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R⁸, R⁹, and R¹⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, one of R⁷ and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ aretaken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴¹.

In some embodiments, R¹¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) is,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R¹¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ aretaken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴¹.

In some embodiments, R¹⁵ is selected from the group consisting of H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and -carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) is, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹⁵ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of H, halide, unsubstituted —(C₁₋₉ alkyl),unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7,1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴¹.

In some embodiments, R¹⁸ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) is,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R¹⁸ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein

In some embodiments, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are takentogether to form a heterocyclyl optionally substituted with 1-10 (e.g.,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰.

In some embodiments, R²¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) is,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R²¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, R²² and R²³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²² and R²³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, R²² and R²³ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R²⁴, R²⁵, and R²⁶ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²⁴, R²⁵, and R²⁶ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, there is the proviso that when R²⁵ is a single bondconnecting R³ to the isoquinoline ring, R²⁴ and R²⁶ are not methyls.

In some embodiments, there is the proviso that when R²⁵ is a single bondconnecting R³ to the isoquinoline ring, R²⁴ and R²⁶ are not bothmethyls.

In some embodiments, there is the proviso that when R²⁵ is a single bondconnecting R³ to the isoquinoline ring, R²⁴ and R²⁶ are not selectedfrom the group consisting of a single bond, H, halide, unsubstituted—(C₁₋₂ alkyl), unsubstituted —(C₂ alkenyl), unsubstituted —(C₂ alkynyl),unsubstituted —(C₁₋₂ haloalkyl).

In some embodiments, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7,1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴¹.

In some embodiments, R²⁷, R²⁸, and R²⁹ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²⁷, R²⁸, and R²⁹ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, R²⁷ and R²⁸ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R³⁰ and R³¹ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³⁰ and R³¹ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, R³⁰ and R³¹ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R³² and R³³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³² and R³³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, each R³⁶ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R³⁶ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R⁴³, —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R⁴⁴, —C(═O)(R⁵⁰), —(C₁₋₄alkylene)C(═O)OR¹, —(C₁₋₄ alkylene)aryl optionally substituted with oneor more halides, —(C₁₋₄ alkylene)_(p)heteroaryl optionally substitutedwith one or more halides (e.g. F, Cl, Br, I), and —SO₂(R⁵²); whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein.

In some embodiments, two R³⁶ that are attached to the same carbon atomcan together represent ═O to form a carbonyl group.

In some embodiments, each R³⁷ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R³⁷ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)OR⁴², —N(R⁵³)₂, —C(═O)(R⁵⁰), —C(═O)OR⁵¹,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³,and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, each R³⁸ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —CN, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R³⁹ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —CN, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R⁴⁰ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —CN, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R⁴¹ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), and —CN.

In some embodiments, each R⁴² is independently selected from the groupconsisting of unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, each R⁴³ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —CN, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R⁴⁴ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), and —CN.

In some embodiments, each R⁴⁵ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein each —(C₁₋₄ alkylene)is, independently, optionally substituted with one or more substituentsas defined anywhere herein.

In some embodiments, each R⁴⁵ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, two adjacent R⁴⁵ groups are taken together to forma ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R⁴⁶ is attached to the nitrogen and is selectedfrom the group consisting of H, unsubstituted —(C₁₋₉ alkyl),unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R⁴⁷ is attached to the nitrogen and is selectedfrom the group consisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) is,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R⁴⁸ is attached to the nitrogen and selected fromthe group consisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted—(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl).

In some embodiments, R⁴⁹ is attached to the nitrogen and is selectedfrom the group consisting of —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R³⁸, and —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R⁵⁰ is selected from the group consisting of H,unsubstituted —(C₃₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)aryl optionally substituted with one or more halides orunsubstituted —(C₁₋₅ alkyl), —(C₁₋₄ alkylene)_(p)heteroaryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl), and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R⁵¹ is selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)aryl optionally substituted with one or more halides orunsubstituted —(C₁₋₅ alkyl), —(C₁₋₄ alkylene)_(p)heteroaryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl), and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R⁵² is selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)aryl optionally substituted with one or more halides orunsubstituted —(C₁₋₅ alkyl), —(C₁₋₄ alkylene)_(p)heteroaryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl), and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, each R⁵³ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), and unsubstituted —(C₂₋₅ alkynyl).

In some embodiments, there is the proviso that Formula I is not astructure selected from the group consisting of:

In some embodiments, the carbocyclyl of —(C₁₋₄ alkylene)_(p)carbocyclylis optionally substituted with 1-12 R³⁷.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄alkylene)_(p)carbocyclyl is optionally substituted with 1-12 R³⁷.

In some embodiments, the heterocyclyl of —(C₁₋₄alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R³⁸.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R³⁸.

In some embodiments, the carbocyclyl of —(C₁₋₄ alkylene)_(p)carbocyclylis optionally substituted with 1-12 R⁴⁴.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄alkylene)_(p)carbocyclyl is optionally substituted with 1-12 R⁴⁴.

In some embodiments, the heterocyclyl of —(C₁₋₄alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R⁴³.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R⁴³.

In some embodiments, —(C₁₋₄ alkylene) is optionally substituted with 1-5halide or 1-5 unsubstituted —(C₁₋₃ alkyl).

In some embodiments, —(C₁₋₄ alkylene) is substituted with 1-2 fluorines.

In some embodiments, —(C₁₋₄ alkylene) is substituted with 1-2 methyls.

In some embodiments, each X is O or S.

In some embodiments, each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, each n is independently 0 to 3 (e.g., 0-2, 0-1, 0).

In some embodiments, each p is independently 0 or 1.

In some embodiments, each q is independently 0 to 12 (e.g., 0-11, 0-10,0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0).

In some embodiments, R³ is

In certain embodiments, R⁹ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R⁷ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R⁷ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R⁷ is selected from the group consisting of H andmethyl.

In some embodiments, R⁷ is methyl.

In some embodiments, R⁷ is —CD₃.

In some embodiments, R⁸ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), unsubstituted —(C₁₋₂ haloalkyl),and —(C₁₋₂ alkylene)OR⁴².

In some embodiments, R⁸ is selected from the group consisting of H, F,methyl, —CF₃, —(CH₂)OH, and —(CH₂)OMe.

In some embodiments, R⁸ is selected from the group consisting of H, F,and methyl.

In some embodiments, R⁸ is H.

In some embodiments, R¹⁰ is selected from the group consisting of H andhalide.

In some embodiments, R¹⁰ is selected from the group consisting of H andF.

In some embodiments, R¹⁰ is H.

In some embodiments, R³ is

In certain embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R¹¹ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R¹¹ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R¹¹ is selected from the group consisting of H andmethyl.

In some embodiments, R¹¹ is methyl.

In some embodiments, R¹¹ is —CD₃.

In some embodiments, R¹³ is selected from the group consisting of H andhalide.

In some embodiments, R¹³ is selected from the group consisting of H andF.

In some embodiments, R¹⁴ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R¹⁴ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R¹⁴ is selected from the group consisting of H andmethyl.

In some embodiments, R¹¹ and R¹⁴ are both methyl.

In some embodiments, R³ is

In some embodiments, R³ is

and X is S.

In some embodiments, R³ is

and X is O.

In certain embodiments, R²⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R²⁸ is selected from the group consisting of H andhalide.

In some embodiments, R²⁸ is selected from the group consisting of H andF.

In some embodiments, R²⁹ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R²⁹ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R³ is

In some embodiments, R³ is

and X is S.

In some embodiments, R³ is

and X is O.

In certain embodiments, R³³ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³² is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), unsubstituted —(C₁₋₂ haloalkyl),and —N(R⁵³)₂.

In some embodiments, R³² is selected from the group consisting of H, F,methyl, —CF₃, —NHMe, and —NMe₂.

In some embodiments, R³² is selected from the group consisting of H andmethyl.

In some embodiments, R³² is methyl.

In some embodiments, R³ is

In certain embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In certain embodiments, R¹⁶ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R¹⁵ is selected from the group consisting of H andunsubstituted —(C₁₋₂ alkyl).

In some embodiments, R¹⁵ is selected from the group consisting of H andmethyl.

In some embodiments, R¹⁵ is methyl.

In some embodiments, R¹⁵ is —CD₃.

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R¹⁸ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R¹⁸ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R¹⁸ is selected from the group consisting of H andmethyl.

In some embodiments, R¹⁹ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R¹⁹ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R³⁹ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₃ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R³⁹ is selected from the group consisting of F,methyl, and —CF₃.

In some embodiments, R⁴⁰ is selected from the group consisting of H andunsubstituted —(C₁₋₂ alkyl).

In some embodiments, R⁴⁰ is selected from the group consisting of H andmethyl.

In some embodiments, R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷.

In some embodiments, R⁶ is a -heterocyclyl optionally substituted with1-2 R³⁶.

In some embodiments, R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R⁶ is a -carbocyclyl optionally substituted with1-2 R³⁷.

In some embodiments, R⁶ is a —(CH₂)carbocyclyl optionally substitutedwith 1-2 R³⁷.

In some embodiments, R⁶ is a —(C₁₋₄ alkylene)N(R⁴⁶)(R⁴⁷).

In some embodiments, R⁶ is a (CH₂)N(R⁴⁶)(R⁴⁷).

In some embodiments, R⁶ is a —(CH₂)NH(C₁₋₅ alkyl).

In some embodiments, R⁶ is a —(CH₂)NH(C₁₋₄ alkyl).

In some embodiments, R⁶ is a —(CH₂)NH(C₁₋₃ alkyl).

In some embodiments, R⁶ is a —(CH₂)NHEt.

In some embodiments, R⁶ is a —(CH₂)NHMe.

In some embodiments, R⁶ is a —(CH₂)NHcarbocyclyl.

In some embodiments, R⁶ is a —(CH₂)NH(CH₂)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₅ alkyl)₂.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₄ alkyl)₂.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₃ alkyl)₂.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₂ alkyl)₂.

In some embodiments, R⁶ is a —(CH₂)NMe₂.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₅ alkyl)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₅ alkyl)(CH₂)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₄ alkyl)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₄ alkyl)(CH₂)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₃ alkyl)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₃ alkyl)(CH₂)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₂ alkyl)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(C₁₋₂ alkyl)(CH₂)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)N(Me)carbocyclyl.

In some embodiments, R⁶ is a —(CH₂)NMe(CH₂)carbocyclyl.

In some embodiments, R⁶ is —CF(C₁₋₉ alkyl)₂; wherein each alkyl of—CF(C₁₋₉ alkyl)₂ is, independently, optionally substituted with one ormore halides.

In some embodiments, R⁶ is —CF(C₁₋₉ alkyl)₂; wherein each alkyl of—CF(C₁₋₉ alkyl)₂ is, independently, optionally substituted with one ormore fluorines.

In some embodiments, R⁶ is —CF(C₁₋₇ alkyl)₂.

In some embodiments, R⁶ is —CF(C₁₋₅ alkyl)₂.

In some embodiments, R⁶ is —CF(C₁₋₄ alkyl)₂.

In some embodiments, R⁶ is —CF(C₁₋₃ alkyl)₂.

In some embodiments, R⁶ is —CF(C₁₋₂ alkyl)₂.

In some embodiments, R⁶ is —CFMe₂.

In some embodiments, R⁶ is —CF(Me)(Et).

In some embodiments, R⁶ is —CFEt₂.

In some embodiments, R⁶ is —CF(Et)(^(n)Pr).

In some embodiments, R⁶ is —CF^(n)Pr₂.

In some embodiments, R⁶ is —CF(Me)(^(n)Pr).

In some embodiments, R⁶ is —CF^(i)Pr₂.

In some embodiments, R⁶ is —CF(Et)(^(i)Pr).

In some embodiments, R⁶ is —CF(Me)(^(i)Pr).

In some embodiments, R³⁶ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₁₋₅ haloalkyl),—(CH₂CH₂)OR⁴², -heterocyclyl optionally substituted with 1-2 R⁴³,—(CH₂)heterocyclyl optionally substituted with 1-2 R⁴³, —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R⁴⁴, and —(CH₂)(C₃₋₄carbocyclyl) optionally substituted with 1-2 R⁴⁴.

In some embodiments, R³⁷ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₁₋₅ haloalkyl),—OR⁴², -heterocyclyl optionally substituted with 1-2 R⁴³, and—(CH₂)heterocyclyl optionally substituted with 1-2 R⁴³.

In some embodiments, the heterocyclyl is selected from the groupconsisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

In some embodiments, R⁴² is selected from the group consisting ofunsubstituted —(C₁₋₃ alkyl), and unsubstituted —(C₁₋₃ haloalkyl).

In some embodiments, R⁴² is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, —CF₃.

In some embodiments, R⁴³ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R⁴³ is selected from the group consisting of F,methyl, ethyl, —CF₃.

In some embodiments, R⁴⁴ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R⁴⁴ is selected from the group consisting of F,methyl, ethyl, —CF₃.

In some embodiments, R³⁶ is selected from the group consisting of F,methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃, —CH₂C(CH₃)₂F, —CH₂CH₂CF₃,—(CH₂CH₂)O(C₁₋₃ alkyl),

In some embodiments, R³⁷ is selected from the group consisting of F,methyl, ethyl, —CF₃, —OCF₃, —OMe,

In some embodiments, R³ is selected from the group consisting of:

where in X is S or O and R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

where in X is S or O and R⁶ is selected from the group consisting of-carbocyclyl optionally substituted with 1-2 R³⁷ and —(CH₂)carbocyclyloptionally substituted with 1-2 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

where in X is S or O and R⁶ is —CF(C₁₋₉ alkyl)₂; wherein the alkyl of—CF(C₁₋₉ alkyl)₂ is optionally substituted with one or more halides.

In some embodiments, R³ is selected from the group consisting of:

where in X is S or O and R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

and R is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is —CF(C₁₋₇ alkyl)₂; wherein the alkyl of —CF(C₁₋₇ alkyl)₂ isoptionally substituted with one or more fluorines.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl each independently optionallysubstituted with 1-2 R³⁷ and —(CH₂)cyclopropyl, —(CH₂)cyclobutyl,—(CH₂)cyclopentyl, and —(CH₂)cyclohexyl, each independently optionallysubstituted with 1-2 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with1-2 R³⁷ and —(CH₂)cyclopropyl, —(CH₂)cyclobutyl, —(CH₂)cyclopentyl, and—(CH₂)cyclohexyl, each optionally substituted with 1-2 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is —CF(C₁₋₅ alkyl)₂; wherein the alkyl of —CF(C₁₋₅ alkyl)₂ isoptionally substituted with 1-4 fluorines.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

q is 1; and R³⁶ is selected from the group consisting of F, methyl,ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃, —CH₂C(CH₃)₂F, —CH₂CH₂CF₃,—(CH₂CH₂)O(C₁₋₃ alkyl),

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

q is 0 to 2, and each R³⁶ is independently selected from the groupconsisting of F, methyl, and —CF₃.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with1-2 R³⁷ and —(CH₂)cyclopropyl, —(CH₂)cyclobutyl, —(CH₂)cyclopentyl, and—(CH₂)cyclohexyl, each optionally substituted with 1-2 R³⁷, and each R³⁷is independently selected from the group consisting of F, methyl, —CF₃,—OCF₃, and —OMe.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

q is 1; and R³⁶ is selected from the group consisting of F, methyl,ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃, —CH₂C(CH₃)₂F, —CH₂CH₂CF₃,—(CH₂CH₂)O(C₁₋₃ alkyl),

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

and, and R³⁶ is selected from the group consisting of methyl, ethyl,isopropyl, isobutyl, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃,—CH₂C(CH₃)₂F, —CH₂CH₂CF₃, —(CH₂CH₂)OMe, —(CH₂CH₂)OiPr,

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶ and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of —(CH₂)heterocyclyloptionally substituted with 1-2 R³⁶-heterocyclyl optionally substitutedwith 1-2 R³⁶, and -carbocyclyl optionally substituted with 1-2 R³⁷, andR³⁶ is selected from the group consisting of halide and unsubstituted—(C₁₋₉ alkyl), and R³⁷ is selected from the group consisting of halideand unsubstituted —(C₁₋₉ alkyl), —N(R⁵³)₂, and -heterocyclyl optionallysubstituted with 1-2 R⁴³.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of —(CH₂)heterocyclyloptionally substituted with 1 R³⁶-heterocyclyl optionally substitutedwith 1 R³⁶, and -carbocyclyl substituted with 1 R³⁷, and R³⁶ isunsubstituted —(C₁₋₅ alkyl), and R³⁷ is selected from the groupconsisting of —N(C₁₋₃ alkyl)₂, and an unsubstituted -heterocyclyl.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

and R³⁶ is selected from the group consisting of methyl, ethyl,isopropyl, isobutyl, —NMe₂, and

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

and R³⁶ is selected from the group consisting of methyl, ethyl,isopropyl, isobutyl, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃,—CH₂C(CH₃)₂F, —CH₂CH₂CH₂F₃, —(CH₂CH₂)OMe, —(CH₂CH₂)OiPr,

In some embodiments, R⁶ is selected from the group consisting of

and R³⁶ is selected from the group consisting of methyl, ethyl,isopropyl, isobutyl, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CF₂CH₃,—CH₂C(CH₃)₂F, —CH₂CH₂CF₃, —(CH₂CH₂)OMe, —(CH₂CH₂)OiPr,

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of:

q is 0 to 2, and each R³⁶ is independently selected from the groupconsisting of F, methyl, and —CF₃.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is selected from the group consisting of -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with1-2 R³⁷ and —(CH₂)cyclopropyl, —(CH₂)cyclobutyl, —(CH₂)cyclopentyl, and—(CH₂)cyclohexyl, each optionally substituted with 1-2 R³⁷, and each R³⁷is independently selected from the group consisting of F, methyl, —CF₃,—OCF₃, and —OMe.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is —CF(C₁₋₃ alkyl)₂; wherein the alkyl of —CF(C₁₋₃ alkyl)₂ isoptionally substituted with 1-2 fluorines.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

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948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

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974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

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1073

1074

1075

1076

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1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) atherapeutically effective amount of a compound provided herein, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula (I) and other another active agentare colorectal cancer, ovarian cancer, chronic inflammation, diabeticretinopathy, pulmonary fibrosis, and osteoarthritis. For example, acompound of Formula (I) can be combined with one or morechemotherapeutic compounds.

In some embodiments, colorectal cancer can be treated with a combinationof a compound of Formula (I) and one or more of the following drugs:5-Fluorouracil (5-FU), which can be administered with the vitamin-likedrug leucovorin (also called folinic acid); capecitabine (XELODA®),irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples ofcombinations of these drugs which could be further combined with acompound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin),FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU,oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).For rectal cancer, chemo with 5-FU or capecitabine combined withradiation may be given before surgery (neoadjuvant treatment).

In some embodiments, ovarian cancer can be treated with a combination ofa compound of Formula (I) and one or more of the following drugs:Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®),Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide(IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine(XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed(ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®).Examples of combinations of these drugs which could be further combinedwith a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide,and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP(etoposide [VP-16], ifosfamide, and cisplatin).

In some embodiments, a compound of Formula (I) can be used to treatcancer in combination with any of the following methods: (a) Hormonetherapy such as aromatase inhibitors, LHRH [luteinizinghormone-releasing hormone] analogs and inhibitors, and others; (b)Ablation or embolization procedures such as radiofrequency ablation(RFA), ethanol (alcohol) ablation, microwave thermotherapy andcryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents suchas cisplatin and carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy usinganti-metabolites such as azathioprine and mercaptopurine; (e)Chemotherapy using plant alkaloids and terpenoids such as vincaalkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) andtaxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposideand docetaxel; (g) Chemotherapy using topoisomerase inhibitors such asirinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide; (h) Chemotherapy using cytotoxic antibiotics such asactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin,idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i)Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate(GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known asZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®),tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax inclinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib,Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in aphase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152,(AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818),MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g.PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy usingmonoclonal antibodies such as Rituximab (marketed as MABTHERA® orRITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab(marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k)radiation therapy.

In some embodiments, diabetic retinopathy can be treated with acombination of a compound of Formula (I) and one or more of thefollowing natural supplements: Bilberry, Butcher's broom, Ginkgo, Grapeseed extract, and Pycnogenol (Pine bark).

In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosiscan be treated with a combination of a compound of Formula (I) and oneor more of the following drugs: pirfenidone (pirfenidone was approvedfor use in 2011 in Europe under the brand name Esbriet®), prednisone,azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan iscurrently being studied in patients with IPF, [The American Journal ofRespiratory and Critical Care Medicine (2011), 184(1), 92-9]),Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal ofPharmacology (2011), 163(1), 141-172], and anti-inflammatory agents suchas corticosteroids.

In some embodiments, a compound of Formula (I) can be used to treatidiopathic pulmonary fibrosis/pulmonary fibrosis in combination with anyof the following methods: oxygen therapy, pulmonary rehabilitation andsurgery.

In some embodiments, a compound of Formula (I) can be used to treatosteoarthritis in combination with any of the following methods: (a)Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen,naproxen, aspirin and acetaminophen; (b) physical therapy; (c)injections of corticosteroid medications; (d) injections of hyaluronicacid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine;(f) in combination with braces and/or shoe inserts or any device thatcan immobilize or support your joint to help you keep pressure off it(e.g., splints, braces, shoe inserts or other medical devices); (g)realigning bones (osteotomy); (h) joint replacement (arthroplasty); and(i) in combination with a chronic pain class.

In some embodiments, macular degeneration can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®),Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) incombination with photodynamic therapy (PDT) or with any of the followingmethods: (a) in combination with laser to destroy abnormal blood vessels(photocoagulation); and (b) in combination with increased vitamin intakeof antioxidant vitamins and zinc.

In some embodiments, retinitis pigmentosa can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurinor with any of the following methods: (a) with the Argus® II retinalimplant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration, including, but not limited to, orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic devices. Insome embodiments, the administration method includes oral or parenteraladministration.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or in combination with aconventional pharmaceutical carrier, excipient or the like.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriermay be prepared. The contemplated compositions may contain 0.001%-100%of a compound provided herein, in one embodiment 0.1-95%, in anotherembodiment 75-85%, in a further embodiment 20-80%. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK.2012).

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a compound provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or morecompounds provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. a compound provided herein andoptional pharmaceutical adjuvants in a carrier (e.g., water, saline,aqueous dextrose, glycerol, glycols, ethanol or the like) to form asolution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of a compound provided herein contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thepatient. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise about 0.1-10% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of theactive agent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 300mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 100mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 10 mg/m² to about 50mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size maybe desired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For delivery to the lung,inhaled aerodynamic particle sizes of about less than 10 μm are useful(e.g., about 1 to about 10 microns). Inhaled particles may be defined asliquid droplets containing dissolved drug, liquid droplets containingsuspended drug particles (in cases where the drug is insoluble in thesuspending medium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intendedfor respiratory delivery (either systemic or local) can be administeredas aqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates, or asdry powders. Aqueous formulations may be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems may use suitablepressurized metered-dose inhalers (pMDIs). Dry powders may use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution may beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed hereincan be administered to the ear by various methods. For example, a roundwindow catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can beused.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the disclosure can be incorporated into agel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intendedfor delivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments the acidic or basic solid compound ofFormula (I) can be delivered from the reservoir of an external orinternal implanted pumping system.

Formulations of the disclosure also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixing acompound provided herein with a suitable non-irritating excipient thatis solid at ordinary temperatures but liquid at the rectal temperatureand will therefore melt or erode/dissolve in the rectum and release thecompound. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, poloxamers, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter, is firstmelted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compoundprovided herein, the desired dissolution rate, cost considerations, andother criteria. In one of the embodiments, the solid composition is asingle unit. This implies that one unit dose of the compound iscomprised in a single, physically shaped solid form or article. In otherwords, the solid composition is coherent, which is in contrast to amultiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In one embodiment, the solid composition is a highly porous lyophilizedform. Such lyophilizates, sometimes also called wafers or lyophilizedtablets, are particularly useful for their rapid disintegration, whichalso enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with a compoundprovided herein so that the compound is located at the outer surface ofthe individual particles. In this type of system, the water-soluble lowmolecular weight excipient may be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, for example, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis,psoriasis, scleroderma, mycotic and viral infections, bone and cartilagediseases, Alzheimer's disease, lung disease, bone/osteoporotic (wrist,spine, shoulder and hip) fractures, articular cartilage (chondral)defects, degenerative disc disease (or intervertebral discdegeneration), polyposis coli, bone density and vascular defects in theeye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, bone and cartilage diseases,neurological conditions/diseases such as Alzheimer's disease,amyotrophic lateral sclerosis (ALS), motor neuron disease, multiplesclerosis or autism, lung disease, bone/osteoporotic (wrist, spine,shoulder and hip) fractures, polyposis coli, bone density and vasculardefects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familialexudative vitreoretinopathy, retinal angiogenesis, early coronarydisease, tetra-amelia, Müllerian-duct regression and virilization,SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly,the compounds and compositions described herein may be used to treatthese cancers in which the Wnt pathway is constitutively activated. Incertain embodiments, the cancer is chosen from hepatocellular carcinoma,colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compounds,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER breast cancer, ER-breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, andcongenital tumors; and cancers of the spinal cord, e.g., neurofibroma,meningioma, glioma, and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenström'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma and metastatic melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

More particularly, tumors of the central nervous system that may betreated by the compounds, compositions and methods described hereininclude:

1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary,protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma,glioblastoma multiforme (giant cell glioblastoma and gliosarcoma),pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphicxanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosiscerebri.

2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplasticoligodendroglioma.

3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplasticoligoastrocytoma.

4) Ependymal tumors, e.g., subependymoma, myxopapillary ependymoma,ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic(malignant) ependymoma.

5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypicalchoroid plexus papilloma, and choroid plexus carcinoma.

6) Neuronal and mixed neuronal-glial tumors, e.g., gangliocytoma,ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplasticgangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplasticinfantile astrocytoma/ganglioglioma, central neurocytoma, anaplasticganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma,Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor of thefourth ventricle, and paraganglioma of the filum terminale.

7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors ofthe pineal region, and pineal parenchymal tumor of intermediatedifferentiation.

8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma withextensive nodularity, anaplastic medulloblastoma, desmoplastic, largecell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorialprimitive neuroectodermal tumors, and primitive neuroectodermal tumors(PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma,and atypical teratoid/rhabdoid tumor.

9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma),olfactory neuroepithelioma, and neuroblastomas of the adrenal gland andsympathetic nervous system.

10) Glial tumors, e.g., astroblastoma, chordoid glioma of the thirdventricle, and angiocentric glioma.

11) Tumors of cranial and paraspinal nerves, e.g., schwannoma,neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.

12) Tumors of the meninges such as tumors of meningothelial cells, e.g.,meningioma (atypical meningioma and anaplastic meningioma); mesenchymaltumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitaryfibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma,leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma,chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma,epithelioid hemangioendothelioma, haemangiopericytoma, anaplastichaemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma;primary melanocytic lesions, e.g., diffuse melanocytosis, melanocytoma,malignant melanoma, meningeal melanomatosis; and hemangioblastomas.

13) Tumors of the hematopoietic system, e.g., malignant Lymphomas,plasmocytoma, and granulocytic sarcoma.

14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sactumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

15) Tumors of the sellar region, e.g., craniopharyngioma, granular celltumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. For example, the compounds described herein can inhibitthe activity of one or more kinases. Accordingly, provided herein is amethod of treating cancer or preventing or reducing angiogenesis throughkinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; fatty liver disease (FLD); adhesions,        such as those occurring in the abdomen, pelvis, spine or        tendons; chronic obstructive pulmonary disease; fibrosis        following myocardial infarction; pulmonary fibrosis; fibrosis        and scarring associated with diffuse/interstitial lung disease;        central nervous system fibrosis, such as fibrosis following        stroke; fibrosis associated with neuro-degenerative disorders        such as Alzheimer's Disease or multiple sclerosis; fibrosis        associated with proliferative vitreoretinopathy (PVR);        restenosis; endometriosis; ischemic disease and radiation        fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, sepsis, ankylosing        spondylitis, psoriasis, scleroderma, autoimmune mediated        glomerulonephritis, inflammatory bowel disease and autoimmune        diabetes mellitus), neuro-degenerative disorders (including but        not limited to Alzheimer's disease, lung disease, amyotrophic        lateral sclerosis, retinitis pigmentosa, Parkinson's disease,        AIDS-related dementia, spinal muscular atrophy and cerebellar        degeneration), myelodysplastic syndromes, aplastic anemia,        ischemic injury associated with myocardial infarctions, stroke        and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteoporosis and        arthritis), tendinopathies such as tendinitis and tendinosis,        aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple        sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, bone density and vascular defects in the        eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial        exudative vitreoretinopathy, retinal angiogenesis, early        coronary disease, tetra-amelia, Müllerian-duct regression and        virilization, SERKAL syndrome, type II diabetes, Fuhrmann        syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,        odonto-onycho-dermal dysplasia, obesity, split-hand/foot        malformation, caudal duplication, tooth agenesis, Wilms tumor,        skeletal dysplasia, focal dermal hypoplasia, autosomal recessive        anonychia, neural tube defects, alpha-thalassemia (ATRX)        syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome,        Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie        disease and Rett syndrome.

The compounds and compositions provided herein have been found topossess immunomodulatory activities and are expected to control theinnate and adaptive immune system (e.g. macrophages, microglia,dendritic cells, B and T cells) and suppress pro-inflammatory cytokinerelease (e.g. TNF, IL-6, IL-1, IFNγ) which is well known to be involvedin chronic inflammation in a wide variety of disease areas. Thereforecompounds and compositions provided herein can used to treat chronicinflammation associated with disorders and diseases including but notlimited to eye disorders, joint pain, arthritis (rheumatoid, osteo,psoriatic gout), cancers (colon, breast, lung, pancreas, and others),gastrointestinal disorders (ulcerative colitis and inflammatory boweldiseases), pulmonary disorders (chronic obstructive pulmonary disorderand asthma), allergies, skin disorders (atopic dermatitis andpsoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heartdisease, myocarditis, stroke, lupus, and neurological disorders such asmultiple sclerosis, Parkinson's and dementia including Alzheimer'sdisease.

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of the enzyme DYRK1A, and thus can be used to treat avariety of disorders and diseases associated with tau protein, amyloid,alpha-synuclein, TDP-43 or FUS pathology including, but not limited to,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), down syndrome,frontotemporal dementia (FTD) including FTD with Parkinsonism-17(FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD inpatients with motor neuron disease (MND) (typically amyotrophic lateralsclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (alsocalled corticobasal ganglionic degeneration), progressive supranuclearpalsy, primary progressive aphasia (PPA), globular glial tauopathy(GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease),myotonic dystrophy type 2 (DM2) (also called proximal myotonicmyopathy), Guam complex, argyrophilic grain disease, dementiapugilistica, post-encephalitic parkinsonism, Lewy body dementia,Parkinson's disease, Pick's disease, and additional diseases withpronounced neurodegeneration such as autism, dementia, epilepsy,Huntington's disease, multiple sclerosis; diseases and disordersassociated with acquired brain injury such as chronic traumaticencephalopathy, traumatic brain injury, tumor, and stroke.

Non-limiting examples of neurological disorders (e.g., neurologicalconditions and neurological diseases) which can be treated with thecompounds and compositions provided herein include Alzheimer's disease,aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attentiondeficit hyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere'sdisease, meningitis, Menkes disease, metachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneuron disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease, and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formula (I), in combination(simultaneously or sequentially) with at least one other agent.

In some embodiments, the disclosure provides a method of treating orameliorating in a patient a disorder or disease selected from the groupconsisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis(IPF), degenerative disc disease, bone/osteoporotic fractures, bone orcartilage disease, and osteoarthritis, the method comprisingadministering to the patient a therapeutically effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the method of treats a disorder or disease in whichaberrant Wnt signaling is implicated in a patient, the method comprisesadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is the pain andinflammation associated with cancer.

In some embodiments, the disorder or disease is the pain andinflammation associated with a joint.

In some embodiments, the disorder or disease is the pain andinflammation associated with the knee.

In some embodiments, the disorder or disease is the pain andinflammation associated with the hip.

In some embodiments, the disorder or disease is the pain andinflammation associated with the shoulder.

In some embodiments, the disorder or disease is the pain andinflammation associated with arthritis.

In some embodiments, the disorder or disease is the pain andinflammation associated with gastrointestinal disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with pulmonary disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with allergies.

In some embodiments, the disorder or disease is the pain andinflammation associated with skin disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with diabetes.

In some embodiments, the disorder or disease is the pain andinflammation associated with pancreatitis.

In some embodiments, the disorder or disease is the pain andinflammation associated with tendonitis.

In some embodiments, the disorder or disease is the pain andinflammation associated with heart disease.

In some embodiments, the disorder or disease is the pain andinflammation associated with lupus.

In some embodiments, the disorder or disease is the pain andinflammation associated with a neurological disorder.

In some embodiments, the disorder or disease is the pain andinflammation associated with multiple sclerosis.

In some embodiments, the disorder or disease is the pain andinflammation associated with Parkinson's.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is systemic inflammation.

In some embodiments, the disorder or disease is metastatic melanoma.

In some embodiments, the disorder or disease is fatty liver disease.

In some embodiments, the disorder or disease is liver fibrosis.

In some embodiments, the disorder or disease is tendon regeneration.

In some embodiments, the disorder or disease is diabetes.

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is idiopathic pulmonaryfibrosis (IPF).

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is a neurological disorder.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease.

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach (gastric) cancers, testicular cancer, thymus cancer,thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer,laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma,gestational trophoblastic disease, gastrointestinal stromal tumor,gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer(melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrialcancer, colorectal cancer, cervical cancer, brain or spinal cord tumor,bone metastasis, bone cancer, bladder cancer, bile duct cancer, analcancer and adrenal cortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach (gastric) cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition, disorder or disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with Lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, multiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis andCharcot-Marie-Tooth disease.

In some embodiments, the disorder or disease is a neurological diseaseor disorder associated with tau protein, amyloid,alpha-synucleinpathology, Tar DNA-binding Protein of 43 KDa (TDP-43), Prion protein PrPor fused in sarcoma (FUS).

In some embodiments, the disorder or disease is selected from the groupconsisting of: Alzheimer's Disease, Amyotrophic Lateral Sclerosis, DownSyndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewybody dementia, Parkinson's Disease, Pick's Disease, and additionaldiseases with pronounced neurodegeneration such as Autism, Dementia,Epilepsy, Huntington's Disease, Multiple Sclerosis; diseases anddisorders associated with acquired brain injury such as ChronicTraumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, a compound of Formula (I) inhibits DYRK1A.

In some embodiments, a compound of Formula (I) inhibits GSK3.

In some embodiments, a compound of Formula (I) inhibits GSK3β.

In some embodiments, a compound of Formula (I) inhibits DYRK1A andGSK313.

In some embodiments, the compound of Formula (I) inhibits one or moreproteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signalinginduced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinaseactivity.

In some embodiments, the method treats a disease or disorder mediated bythe Wnt pathway in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or moreWnt proteins.

In some embodiments, the method treats a disease or disorder mediated bykinase activity in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient; the method comprisesadministering to the patient a therapeutically effective amount of acompound (or compounds) of Formula (I), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) of Formula(I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient, the method comprisesadministering to the patient a pharmaceutical composition comprising oneor more of the compounds of claim 1 in combination with apharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe cyclin-dependent kinases (CDKs), can modulate the level of cellularRNA and DNA synthesis and therefore are expected to be useful in thetreatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and thelike.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀ or G₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, see, e.g.,WO 2001/053268 and WO 2005/009997. For example, the activity of acompound may be tested using one or more of the test methods outlinedbelow.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a candidate inhibitor with cells containingconstitutively active Wnt/β-catenin signaling. The cells are culturedfor a period of time sufficient to stabilize β-catenin, usually at leastabout 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

In another example, in vitro assays for DYRK1A biological activity maybe used, e.g. regulation of microtubule-associated protein tau(MAPT/Tau) phosphorylation in neuronal cell line such as the humanSH-SY5Y neuroblastoma cell line. Assays for DYRK1A-regulated level ofphosphorylation can include monitoring levels of basal pSer396 Tau,which can be measured, for example, by serial dilutions of a candidateinhibitor composition using a ten micromolar top concentration anddetected by ELISA or Western Blotting. An exemplary assay forDYRK-1A-regulated phosphorylation uses the SH-SY5Y cells cultured in a96 well plate format for a period of time sufficient to stabilizemicrotubules and Tau phosphorylation, usually at least 2 days, thentreated with a ⅓ serial dilution of compounds overnight and lysed. Thecell lysate is resolved by SDS PAGE, then transferred to nitrocelluloseand probed with an antibody specific for pSer396 Tau. Thechemiluminescence signal for HRP-linked antibodies used in westernblotting is detected using a Carestream Image Station and blotdensitometry for pSer396 and beta-actin are analyzed using ImageJ (NIH).

In a further example, the activity of a candidate compound can bemeasured by ELISA by adding the lysate mentioned above onto totalTau-coated plates and detected with a specific pSer396 antibody.Colorimetric detection of ELISA signal is performed by Cytation3 platereader (Biotek).

To further illustrate this disclosure, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the disclosure. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the disclosure asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the disclosure without exhaustive examples.

EXAMPLES Compound Preparation

The starting materials used in preparing the compounds of the disclosureare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in P. Wuts Greene's ProtectiveGroups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014),incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the disclosure. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the disclosure.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets ofdoublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td,triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

-   -   brine=saturated aqueous sodium chloride    -   CDCl₃=deuterated chloroform    -   DCE=dichloroethane    -   DCM=dichloromethane    -   DIPEA=N,N-diisopropylethylamine    -   DMAP=4-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO-d₆=deuterated dimethylsulfoxide    -   ESIMS=electron spray mass spectrometry    -   EtOAc=ethyl acetate    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HCl=hydrochloric acid    -   HOAc=acetic acid    -   ISCO=Teledyne ISCO, Inc brand CombiFlash® Rf200    -   KOAc=potassium acetate    -   LAH=Lithium aluminium hydride    -   LC/MS=Liquid chromatography-mass spectrometry    -   MeCN=acetonitrile    -   MeOH=methanol    -   MgSO₄=magnesium sulfate    -   MsCl=mesyl chloride or methanesulfonyl chloride    -   MTBE=methyl tert-butyl ether    -   MW=microwave irradiation    -   NaBH₃CN=sodium cyanoborohydride    -   NaHCO₃=sodium bicarbonate    -   Na(OAc)₃BH=Sodium triacetoxyborohydride    -   NMR=nuclear magnetic resonance    -   ON=overnight    -   Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride    -   Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)    -   r.t.=room temperature    -   SPhos Pd        G3=[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate methanesulfonate    -   SPhos Pd        G4=Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)    -   TBAF=Tetra-n-butylammonium fluoride,    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the disclosure will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I of the present disclosure can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IX) by first coupling the aminewith a variety of acids (III) to produce amide IV. The bromo derivativeIV is then reacted with bis(pinacolato)diboron to give the pinacol ester(V). Suzuki coupling with a variety of 5-membered heteroaryl bromides(VIII) yields the desired R³ substituted isoquinoline IX. Alternatively,the bromo derivative IV is Suzuki coupled with a variety of 5-memberedheteroaryl pinacol esters (VI) or coupled to a variety of 5-memberedheteroaryl stannanes (VII) to produce the final R³ substitutedisoquinoline IX.

In some embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 2.

Scheme 2 describes a method for preparation ofisoquinoline-3-carboxamide intermediate (IVa) by first coupling theamine 4-nitrophenyl carbonochloridate followed by coupling with avariety of R⁶ NH heterocyclyls. Intermediate IVa could then be used inplace of IV in Scheme 1 or 3.

In other embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 3.

Scheme 3 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IXa) starting with bromointermediate IV or IVa and couple with the nitrogen of a variety of R³NH heteroaryls to produce the final R³ substituted isoquinoline IXa.

Illustrative Compound Examples

Preparation of intermediate 6-bromoisoquinolin-1-d-3-amine (XI) isdepicted below in Scheme 4.

Step 1

To a mixture of 1,6-dibromoisoquinolin-3-amine (X) (0.5 g, 1.66 mmol),ammonium formate-d₅ (0.56 g, 8.28 mmol) and Pd(PPh₃)₄ (191.3 mg, 0.170mmol) in DMF (5 mL) was heated to 50° C. for 48 h. The solvents wereconcentrated and the residue was suspended in chloroform. The solid wascollected by filtration and washed with water and EtOAc. The solid weredried under high vacuo to obtain 6-bromo-1-deuterio-isoquinolin-3-amine(XI) (115 mg, 0.513 mmol, 31.0% yield) as a pale yellow solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 6.11 (2H, s), 6.55 (1H, s), 7.22 (1H, dd,J=8.78, 1.92 Hz), 7.73 (1H, d, J=8.51 Hz), 7.79 (1H, d, J=1.92 Hz);ESIMS found for C₉H₆DBrN₂ m/z 224.0 (⁷⁹BrM+H).

Preparation of intermediate 6-bromo-4-chloroisoquinolin-3-amine (XIII)is depicted below in Scheme 5.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (1.0 g, 4.48mmol) in DMF (15 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione(598.6 mg, 4.48 mmol) portionwise. The mixture was stirred at 0° C. for6 h. The reaction mixture was added to water (150 mL), stirred for 1 hand the resulting solids were collected by filtration and air driedovernight to obtain 6-bromo-4-chloro-isoquinolin-3-amine (XIII) (922 mg,3.58 mmol, 79.9% yield) as a beige solid which was used for next stepwithout purification. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.55 (2H, s), 7.40(1H, dd, J=8.64, 1.78 Hz), 7.88 (1H, d, J=8.51 Hz), 7.90 (1H, d, J=1.10Hz), 8.86 (1H, s); ESIMS found for C₉H₆BrClN₂ m/z 256.9 (⁷⁹BrM+H).

Preparation of intermediate 6-bromo-4-methylisoquinolin-3-amine (XV) isdepicted below in Scheme 6.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (2.g, 8.97mmol) in DMF (25.1 mL) at 0° C. was added 1-iodopyrrolidine-2,5-dione(2.02 g, 8.97 mmol) portionwise, The mixture was stirred at 0° C. for 1hr. LC-MS of the mixture showed completion of the reaction and thedesired product. The solvent was removed under vacuum, the residue waspurified by C18 Silica gel (240 g) [0→100% H₂O/MeCN (0.1% Formic acid)]to produce 6-bromo-4-iodo-isoquinolin-3-amine (XIV) (1.95 g, 5.58 mmol,62.2% yield) as a brown solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.41 (2H,br s), 7.40 (1H, dd, J=8.64, 1.78 Hz), 7.76-7.81 (1H, m), 7.82 (1H, d,J=8.51 Hz), 8.81 (1H, s); ESIMS found for C₉H₆BrlN₂ m/z 348.9 (⁷⁹BrM+H).

Step 2

A stirred solution of 6-bromo-4-iodo-isoquinolin-3-amine (XIV) (1.0 g,2.87 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.72 g, 2.87mmol), Pd(dppf)Cl₂ (0.23 g, 0.29 mmol), and K₃PO₄ (5.73 mL, 5.73 mmol)in 1,4-dioxane (10 mL) was heated to 90° C. for 3 days. The solvent wasremoved under high vacuum and the residue was purified by C18 silica gel(240 g) [0→20% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-4-methyl-isoquinolin-3-amine (XV) (74 mg, 0.312 mmol, 10.9%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.23 (3H,br s), 5.91 (2H, br s), 7.27 (1H, br d, J=2.20 Hz), 7.71-7.82 (1H, m),7.92 (1H, br s), 8.72 (1H, br s); ESIMS found for C₁₀H₉BrN₂ m/z 239.0(⁸¹BrM+H).

Preparation of intermediate 6-bromo-7-fluoroisoquinolin-3-amine (XVIII)is depicted below in Scheme 7.

Step 1

To a vial was added 2,2-diethoxyacetonitrile (XVI) (1.0 g, 7.74 mmol)dissolved MeOH (7.74 mL) followed by addition of MeONa/MeOH (0.18 mL,0.77 mmol) dropwise. The reaction was stirred at room temperature for 20h. HOAc (44.3 μL, 0.77 mmol) was added until pH=7-8 (using pH strips).(4-Bromo-3-fluoro-phenyl)methanamine hydrochloride (XVII) (1.86 g, 7.74mmol) was added and stirred at 40° C. for 4 h. The solvent was removedunder vacuum. Sulfuric acid (12.6 mL, 232.3 mmol) was added and stirredat 40° C. for 16 h. NH₄OH (30.8 mL, 240.0 mmol) was added dropwise at 0°C. The solvent was removed under vacuum and the residue was purified byC18 silica gel (240 g) [0→50% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-7-fluoro-isoquinolin-3-amine (XVIII) (1.33 g, 5.50 mmol, 71.1%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.07 (2H,s), 6.61 (1H, s), 7.76 (1H, d, J=9.33 Hz), 8.01 (1H, d, J=6.86 Hz), 8.80(1H, s); ESIMS found for C₉H₆BrFN₂ m/z 242.9 (⁸¹BrM+H).

Preparation of intermediates 6-bromo-7-chloroisoquinolin-3-amine (XX)and 6-bromo-5-chloroisoquinolin-3-amine (XXI) is depicted below inScheme 8.

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.59 g, 4.57mmol) in a vial containing MeOH (4.57 mL) was added MeONa (0.1 mL, 0.46mmol) dropwise. The reaction was stirred at 35° C. for 20 h. HOAc wasadded (26.1 μL, 0.46 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-chloro-phenyl)methanamine (XIX) (1.01 g, 4.57mmol). The mixture was stirred at 35° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (7.43 mL, 137.0 mmol) was then addedand stirred at 35° C. for 16 h. NH₄OH (60.6 mL, 141.6 mmol) was added at0° C. The reaction was filtered through Celite and purified by C18silica gel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1mixture (by nmr) of 6-bromo-7-chloro-isoquinolin-3-amine (XX) and6-bromo-5-chloroisoquinolin-3-amine (XXI) (633.7 mg, 2.46 mmol, 53.9%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.23 (2H, s), 6.46 (2H, s), 6.57(1H, s), 6.83 (1H, s), 7.40 (1H, d, J=8.51 Hz), 7.74 (1H, d, J=8.51 Hz),8.05 (1H, s), 8.09 (1H, s), 8.81 (1H, s), 8.88 (1H, s); ESIMS found forC₉H₆BrClN₂ m/z 256.9 (⁷⁹BrM+H).

Preparation of intermediates 6-bromo-7-methylisoquinolin-3-amine (XXIII)and 6-bromo-5-methylisoquinolin-3-amine (XXIV) is depicted below inScheme 9.

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.33 g, 2.52mmol) in a vial containing MeOH (2.52 mL) was added MeONa (0.23 mL, 0.25mmol) dropwise. The reaction was stirred at 22° C. for 20 h. HOAc wasadded (14.4 μL, 0.25 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-methyl-phenyl)methanamine (XXII) (0.5 g, 2.52mmol). The mixture was stirred at 40° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (4.09 mL, 75.49 mmol) was then addedand stirred at 40° C. for 16 h. NH₄OH (33.4 mL, 78 mmol) was added at 0°C. The reaction was filtered through Celite and purified by C18 silicagel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1 mixture(by nmr) of 6-bromo-7-methylisoquinolin-3-amine (XXIII) and6-bromo-5-methylisoquinolin-3-amine (XXIV) (378 mg, 1.59 mmol, 63.4%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.40 (3H, s), 2.52 (3H, s), 5.96(2H, s), 6.12 (1H, s), 6.54 (1H, s), 6.71 (1H, s), 7.27 (1H, d, J=8.78Hz), 7.58 (1H, d, J=8.78 Hz), 7.73 (1H, s), 7.86 (1H, s), 8.74 (1H, s),8.79 (1H, s); ESIMS found for C₁₀H₉BrN₂ m/z 237.0 (⁷⁹BrM+H).

Preparation of intermediate 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (XXVII) is depicted below in Scheme 10.

Step 1

1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (XXV) (3.7334 g, 24.23mmol) was dissolved in THF (162 mL) and cooled to 0° C. LAH (1.1614 g,29.07 mmol) was then added and the reaction heated to 40° C. overnight.The reaction was cooled to 0° C. Water (2 mL) was added to quench thereaction followed by 2 N NaOH (0.3 mL). The reaction was stirred forminga precipitate which was filtered off and washed with ether. The aqueousphase was removed and the organic phase was washed with brine, dried,and carefully concentrated to give(1-(trifluoromethyl)cyclopropyl)methanol (XXVI) (1.5376 g, 10.98 mmol,45.3% yield) as a clear, volatile liquid.

Step 2

To a solution of (1-(Trifluoromethyl)cyclopropyl)methanol (XXVI) (1.6 g,11.42 mmol) in DCM (23 mL) was added Et₃N (1.9 mL, 13.7 mmol). Thereaction was cooled to 0° C. and MsCl was added dropwise. The reactionwas stirred at 0° C. for 1 h. The reaction was poured into water, andextracted with DCM. The organic phase was separated, washed with brine,dried, and concentrated. The crude mesylate was then dissolved inacetone (22 mL). LiBr (4.96 g, 57.1 mmol) was added, and the reactionstirred at room temperature overnight. The acetone was carefullyremoved, and the residue was partitioned between water and ether. Theaqueous phase was separated and reextracted with ether. The organicphases were combined, washed with brine, dried, and carefullyconcentrated to give 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane(XXVII) (1.2867 g, 6.34 mmol, 55.5% yield) as a gold liquid withresidual amounts of acetone. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.04 (2H,tquin, J=5.17, 5.17, 1.74, 1.74, 1.74, 1.74 Hz), 1.23-1.27 (2H, m), 3.77(2H, s).

Example 1

Preparation ofN-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide(271) is depicted below in Scheme 11.

Step 1

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (XXVIII) (1.542 g, 6.72 mmol) and HATU (2.56 g, 6.72 mmol) wasadded DIPEA (2.349 mL, 13.45 mmol). After 10 min,6-bromoisoquinolin-3-amine (XII) (1 g, 4.48 mmol) was added followed bythe addition of DMAP (0.110 g, 0.897 mmol) and the mixture was heated to70° C. overnight. The LC/MS of mixture showed complete conversion of theamine to the product. The solvents were concentrated in vacuo, theresidue taken into EtOAc, washed with water, sat. aq. NaHCO₃ and brinesolution. The organic layer was dried over anhydrous Na₂SO₄, solventsremoved in vacuo and the residue was dried under high vacuo to obtaincrude tert-butyl4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate (XXIX) asa brown gummy solid (2.29 g, 5.27 mmol, 11.8% yield). Used for next stepwithout purification.

Step 2

To a stirred solution of tert-butyl4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate (XXIX)(1.0 g, 2.302 mmol) in DCM (4.0 mL) was added TFA (4.0 mL, 51.9 mmol)dropwise and the mixture was stirred at room temperature for 2 h. Thesolvent were evaporated in vacuo, the residue was neutralized with 7 NNH₃/MeOH, concentrated and dried under high vacuo to obtainN-(6-bromoisoquinolin-3-yl)piperidine-4-carboxamide as a dark brownsolid (0.769 g, 2.302 mmol, 100% yield). Used for next step withoutpurification. ESIMS found for C₁₅H₁₆BrN₃O m/z 336.1 (⁸¹BrM+H).

Step 3

To a stirred suspension ofN-(6-bromoisoquinolin-3-yl)piperidine-4-carboxamide (0.769 g, 2.30 mmol)and potassium carbonate (1.271 g, 9.20 mmol) in MeCN (10 ml) was added1,1,1-trifluoro-3-iodopropane (0.270 mL, 2.300 mmol). The mixture wasthen heated to 90° C. overnight. Another equivalents of1,1,1-trifluoro-3-iodopropane (0.270 mL, 2.300 mmol) was added andheating continued at 90° C. over a 2^(nd) night. The reaction mixturewas absorbed on silica and was purified by ISCO using EtOAc/hexanes(0→100%) and then with CHCl₃/MeOH (0→100% to recover unreacted startingmaterial). The pure fractions were combined, concentrated, the residuesuspended in diethylether, sonicated and the solid were collected byfiltration and dried under high vacuo to obtainN-(6-bromoisoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide(XXX) as an off-white solid (0.31 g, 0.720 mmol, 31.3% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 1.57-1.71 (m, 2H), 1.79 (br d, J=11.80 Hz, 2H),1.89-2.01 (m, 2H), 2.41-2.60 (m, 5H), 2.88-2.98 (m, 2H), 7.63 (dd,J=8.78, 1.92 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.18 (d, J=1.37 Hz, 1H),8.45 (s, 1H), 9.14 (s, 1H), 10.61 (s, 1H); ESIMS found for C₁₈H₁₉BrF₃N₃Om/z 432.3 (⁸¹BrM+H).

Step 4

To a solution of N-(6-bromoisoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide (XXX) (0.170 g, 0.395 mmol),bis(pinacolato)diboron (0.150 g, 0.593 mmol), potassium acetate (0.116g, 1.185 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ adduct (0.032 g, 0.040 mmol) wastaken in dioxane (2.5 mL). N₂ gas was bubbled into the mixture for 10min and then the mixture was heated to 95° C. for 5 h to produceN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide (XXXI). ESIMS found for C₂₄H₃₁BF₃N₃O₃ m/z 478.1(M+1). Use for next step without work up or further purification.

Step 5

To the above solution was added 4-bromo-1-methyl-1H-1,2,3-triazole(XXXII) (0.064 g, 0.395 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (0.032 g, 0.040mmol) and 2 M aqueous solution of potassium carbonate (0.395 mL, 0.790mmol). The reaction mixture was heated overnight at 95° C. The reactionmixture was absorbed on silica and purified by ISCO using CHCl₃/7N NH₃in MeOH (0→5%) followed by preparative TLC to obtainN-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide (271) as a beige solid (0.011 g, 0.025 mmol,6.44% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.60-1.73 (m, 2H),1.76-1.84 (m, 2H), 1.92-2.01 (m, 2H), 2.41-2.60 (m, 5H), 2.94 (br d,J=11.25 Hz, 2 H), 4.14 (s, 3H), 8.01 (dd, J=8.51, 1.37 Hz, 1H), 8.11 (d,J=8.51 Hz, 1H), 8.28 (s, 1H), 8.50 (s, 1H), 8.73 (s, 1H), 9.11 (s, 1H),10.55 (s, 1H); ESIMS found for C₂₁H₂₃F₃N₆O m/z 433.2 (M+1).

Example 2

Preparation ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide (86) is depicted below in Scheme 12.

Step 1

To a solution ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide(72) (0.095 g, 0.283 mmol) in MeOH (1.5 mL) was added oxetan-3-one(0.027 mL, 0.425 mmol) followed by the addition of HOAc (0.081 mL, 1.416mmol). The mixture was stirred for 20 min, then, sodium cyanoborohydride(0.027 g, 0.425 mmol) was added and the reaction mixture was stirred atroom temperature overnight. The solvent was removed in vacuo, theresidue partitioned between EtOAc/sat. aq. NaHCO₃, the organic layerseparated, washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄, solvents removed in vacuo and the crude product waspurified by ISCO (0→5% CHCl₃/7 N NH₃ in MeOH). The pure fractions werecombined, concentrated, the residue suspended in DCM, sonicated and thesolids were collected by filtration to obtainN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide(86) off-white solid (62.0 mg, 0.158 mmol, 56.0% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 1.62-1.73 (m, 2H), 1.74-1.86 (m, 4H), 2.52-2.60(m, 1H), 2.71-2.80 (m, 2H), 3.38 (quin, J=6.45 Hz, 1H), 3.90 (s, 3H),4.43 (t, J=6.17 Hz, 2H), 4.53 (t, J=6.59 Hz, 2H), 7.74 (dd, J=8.51, 1.37Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s,1H), 8.45 (s, 1H), 9.02 (s, 1H), 10.48 (s, 1H); ESIMS found forC₂₂H₂₅N₅O₂ m/z 392.2 (M+1).

Example 3

Preparation ofN-(6-(5-(Dimethylamino)-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide(1075) and N-(6-(5-(dimethylamino)-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide (1076) is depictedbelow in Scheme 13.

Step 1

To a mixture of tert-butyl4-[(6-bromo-3-isoquinolyl)carbamoyl]piperidine-1-carboxylate (XXXIII) (1g, 2.3 mmol), NaOAc (566.6 mg, 6.91 mmol), molybednumhexacarbonyl (953mg, 3.45 mmol) and Pd(dppf)Cl₂ (376 mg, 0.46 mmol) in MeOH (20 mL) washeated to 75° C. overnight. The reaction mixture was absorbed on silicagel and was purified by column chromatography using (25%→100%EtOAc/hexanes) to obtain methyl3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylate(XXXIV) (950 mg, 2.30 mmol, 99.8% yield) as a grey solid. ESIMS foundfor C₂₂H₂₇N₃O₅ m/z 414.2 (M+1).

Step 2

To a stirred solution of methyl3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylate(XXXIV) (950.mg, 2.3 mmol) in MeOH (15 mL) was added 2N aqueous solutionof NaOH (2.3 mL, 4.6 mmol) and the mixture was heated to 50° C. Thereaction mixture was concentrated, the residue taken up in water andacidified with 1N HCl and the resulting solid was collected byfiltration, washed with water and dried under high vacuo to obtain3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylicacid (XXXV) (900 mg, 2.25 mmol, 98.1% yield) as a brown solid. ESIMSfound for C₂₁H₂₅N₃O₅ m/z 400.2 (M+1).

Step 3

To a mixture of3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylicacid (XXXV) (0.5 g, 1.26 mmol), HATU (0.48 g, 1.26 mmol) andN-ethyl-N-isopropyl-propan-2-amine (0.66 mL, 3.77 mmol) in DMF (10 mL)was stirred for 10 min. Then 3-amino-1, 1-dimethylthiourea (0.18 g, 1.51mmol) was added and the mixture was stirred at room temperature for 5 h.The reaction mixture was concentrated, the residue taken in CHCl₃,washed with sat. NaHCO₃, H₂O and brine. The organic layer was separatedand dried (MgSO₄) before concentration to dryness to obtain tert-butyl4-[[6-[(dimethylcarbamothioylamino)carbamoyl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate(XXXVI) (600 mg, 1.20 mmol, 95.4% yield) as a brown solid which was usedfor next step without purification. ESIMS found for C₂₄H₃₂N₆O₄S m/z501.2 (M+1).

Step 4

To a mixture of tert-butyl4-[[6-[(dimethylcarbamothioylamino)carbamoyl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate(XXXVI) (600 mg, 1.2 mmol),2-chloro-1,3-dimethyl-4,5-dihydroimidazol-1-ium chloride (405.2 mg, 2.4mmol) and N,N-diethylethanamine (0.5 mL, 3.6 mmol) in DCM (10 mL) wasstirred overnight at room temperature. Reaction mixture was concentratedand the residue was purified by column chromatography (0-+10%7N—NH₃-MeOH/CHCl₃) to obtain tert-butyl4-[[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate(XXXVII) (60 mg, 0.129 mmol, 10.7% yield) as a brown solid. ESIMS foundfor C₂₄H₃₀N₆O₄ m/z 467.2 (M+1).

Step 5

To a stirred solution of tert-butyl4-[[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate(XXXVII) (60 mg, 0.130 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.57mmol) and the mixture was stirred at room temperature for 5 h. Reactionmixture was concentrated and the residue was absorbed on silica gel,purified by flash column chromatography (0-10% 7N—NH₃-MeOH/CHCl₃) toobtainN-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]piperidine-4-carboxamide(1075) (32 mg, 0.087 mmol, 67.9% yield) as a white solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.54 (2H, qd, J=12.17, 4.12 Hz), 1.71 (2H, br d,J=10.43 Hz), 2.44-2.49 (2H, m), 2.65 (1H, tt, J=11.49, 3.60 Hz), 2.98(2H, br d, J=12.08 Hz), 3.13 (6H, s), 7.96 (1H, dd, J=8.51, 1.65 Hz),8.15 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.59 (1H, s), 9.17 (1H, s), 10.55(1H, s); ESIMS found for C₁₉H₂₂N₆O₂ m/z 367.2 (M+1).

Step 6

To a mixture ofN-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]piperidine-4-carboxamide(1075) (27 mg, 0.070 mmol), NaBH₃CN (14.03 mg, 0.070 mmol) and catalyticHOAc in MeOH (2 mL) was stirred for 30 min, formaldehyde (2.21 mg, 0.070mmol) was added and the stirring was continued 2 h. The reaction mixturewas quenched with minimum amount of aq. saturated NH₄Cl, concentrated onunder vacuum and the residue was adsorbed on silica gel, purified bychromatography (0→20% 7N.NH₃-MeOH/CHCl₃) to obtainN-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]-1-methyl-piperidine-4-carboxamide(1076) (25 mg, 0.066 mmol, 89.2% yield) as a white solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.62-1.74 (2H, m), 1.74-1.81 (2H, m), 1.87 (2H, td,J=11.66, 2.20 Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.77-2.85 (2H, m),3.13 (6H, s), 7.96 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz),8.35 (1H, s), 8.59 (1H, s), 9.18 (1H, s), 10.61 (1H, s); ESIMS found forC₂₀H₂₄N₆O₂ m/z 381.2 (M+1).

Example 4

Preparation ofN-(6-(1H-1,2,3-triazol-1-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide(1074) andN-(6-(2H-1,2,3-triazol-2-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide(1075) is depicted below in Scheme 14.

Step 1

To a mixture of 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylicacid (XXXVIII) (1.07 mL, 13.99 mmol), HATU (7.09 g, 18.65 mmol) andDIPEA (4.87 mL, 27.97 mmol) in DMF (40 mL) was stirred for 10 min. Then,6-bromoisoquinolin-3-amine (XII) (2.08 g, 9.32 mmol) and DMAP (0.23 g,1.86 mmol) was added then the mixture was heated to 80° C. overnight.The reaction mixture was concentrated, the residue partitioned betweenEtOAc/sat.NaHCO₃, organic layer separated, washed with water and brine.The organics were then separated and dried (MgSO₄) before concentrationto dryness. The crude was then purified by flash column chromatography(0→40% EtOAc/hexanes). The desired fractions were concentrated todryness en vacuo and recrystallized with hexanes to obtain tert-butyl4-[(6-bromo-3-isoquinolyl)carbamoyl]-4-fluoro-piperidine-1-carboxylate(XXXIX) (2.94 g, 6.50 mmol, 69.7% yield) as a white solid. ESIMS foundfor C₂₀H₂₃BrFN₃O₃ m/z 452.1 (⁷⁹BrM+1).

Step 2

To a suspension of tert-butyl4-[(6-bromo-3-isoquinolyl)carbamoyl]-4-fluoro-piperidine-1-carboxylate(XXXIX) (1.92 g, 4.24 mmol) in DCM (8 mL) was added TFA (8.mL, 103.84mmol) at 0° C. and the mixture was stirred for 1 h. The solvents wereconcentrated, triturated with CHCl₃ (3×) and the resulting solids weredried under high vacuo to obtainN-(6-bromo-3-isoquinolyl)-4-fluoro-piperidine-4-carboxamide (XL) (1.979g, 4.24 mmol, 100% yield) as an off-white solid which was used for nextstep without further purification. ESIMS found for C₁₅H₁₅BrFN₃O m/z352.0 (⁷⁹BrM+1).

Step 3

To a suspension ofN-(6-bromo-3-isoquinolyl)-4-fluoro-piperidine-4-carboxamide (XL) (1.98g, 4.24 mmol) in MeCN (20 mL) was added 1-iodo-2-methyl-propane (0.98mL, 8.48 mmol) and the mixture was stirred for 30 min. The solvents wereconcentrated, treated with 7N NH₃/MeOH, absorbed on silica gel andpurified by column chromatography (0→30% CHCl₃/10% 7N NH₃ MeOH) toobtainN-(6-bromo-3-isoquinolyl)-4-fluoro-1-isobutyl-piperidine-4-carboxamide(XLI) (1.4 g, 3.43 mmol, 80.9% yield) as a beige solid. ESIMS found forC₁₉H₂₃BrFN₃O m/z 408.1 (⁷⁹BrM+1).

Step 4

To a mixture ofN-(6-bromo-3-isoquinolyl)-4-fluoro-1-isobutyl-piperidine-4-carboxamide(XLI) (150 mg, 0.370 mmol), 1H-triazole (0.04 mL, 0.730 mmol), Cs₂CO₃(239 mg, 0.730 mmol), N,N-dimethylethylenediamine (6.48 mg, 0.070 mmol)and CuI (0.mL, 0.040 mmol) in DMF (2 mL) was purged with N₂ gas for 10min. The mixture was then heated to 120° C. overnight. The reactionmixture was filtered through Celite and to the filtrates, water wasadded and extracted with EtOAc. The organics were separated, washed withbrine, dried over anhydrous Na₂SO₄, and evaporated under vacuo. Thecrude products were purified by RP-HPLC. The pure fractions werecombined and dried under vacuum to obtainN-(6-(2H-1,2,3-triazol-2-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide(1073) (3.5 mg, 0.008 mmol, 2.2% yield) as an off-white solid; ¹H NMR(499 MHz, DMSO-d₆) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dquin,J=13.55, 6.84, 6.84, 6.84, 6.84 Hz), 1.92-2.02 (2H, m), 2.05-2.21 (6H,m), 2.75-2.82 (2H, m), 8.25 (2H, s), 8.26-8.29 (1H, m), 8.29-8.33 (1H,m), 8.52 (1H, d, J=1.37 Hz), 8.56 (1H, s), 9.25 (1H, s), 10.02 (1H, brd, J=3.29 Hz); ESIMS found for C₂₁H₂₅FN₆O m/z 397.0 (M+1) andN-(6-(1H-1,2,3-triazol-1-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide(1074) (2 mg, 0.005 mmol, 1.2% yield) as an off-white solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dquin, J=13.46,6.79, 6.79, 6.79, 6.79 Hz), 1.92-2.02 (2H, m), 2.06-2.12 (2H, m),2.12-2.21 (4H, m), 2.73-2.83 (2H, m), 8.06 (1H, d, J=1.10 Hz), 8.19 (1H,dd, J=8.92, 2.06 Hz), 8.34 (1H, d, J=9.06 Hz), 8.53 (1H, d, J=1.92 Hz),8.58 (1H, s), 9.03 (1H, d, J=1.10 Hz), 9.28 (1H, s), 10.07 (1H, br d,J=3.84 Hz); ESIMS found for C₂₁H₂₅FN₆O m/z 397.0 (M+1).

Example 5

Preparation oftrans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide(1064) is depicted below in Scheme 15.

Step 1

To a mixture of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid (XLII) (1.15 mL, 56.04 mmol), HATU (21.31 g, 56.04 mmol),6-bromoisoquinolin-3-amine (XII) (10.g, 44.83 mmol), and DMAP (1.1 g,8.97 mmol) in DMF (100 mL) was added DIPEA (23.4 mL, 134.49 mmol). Themixture was stirred at 70° C. overnight. The reaction mixture was cooledbefore water (800 mL) was added and stirred for ˜2 h. The solid wascollected by filtration and sequentially washed with aq. sat.NH₄Cl,water and aq. sat.NaHCO₃. The solid was dried under high vacuo to obtaintert-butyltrans-N-[4-[(6-bromo-3-isoquinolyl)carbamoyl]cyclohexyl]carbamate(XLIII) (17.87 g, 39.86 mmol, 88.9% yield) as a grey solid which wasused for next step without further purification. ESIMS found forC₂₁H₂₆BrN₃O₃ m/z 448.1 (⁷⁹BrM+1).

Step 2

To a stirred solution of tert-butyl trans-N-[4-[(6-bromo-3-isoquinolyl)carbamoyl]cyclohexyl]carbamate (XLIII) (5.g, 11.15 mmol) in DCM (20 mL)was added TFA (10 mL, 129.8 mmol). The mixture was stirred for 1 h at25° C. The solvent was concentrated and the residue was treated with 7NNH₃/MeOH. The crude product was purified by column chromatography(25→100% CHCl₃/10% 7N NH₃ MeOH in CHCl₃). The pure fractions werecombined, concentrated, the residue suspended in EtOAc, sonicated andthe solid was collected by filtration, washed with diethyl ether anddried under high vacuo to obtaintrans-4-amino-N-(6-bromo-3-isoquinolyl)cyclohexanecarboxamide (XLIV) (3g, 8.61 mmol, 77.2% yield) as a beige solid. ESIMS found for C₁₆H₁₈BrN₃Om/z 348.1 (⁷⁹BrM+1).

Step 3

To a mixture of trans-4-amino-N-(6-bromo-3-isoquinolyl)cyclohexanecarboxamide (XLIV) (550 mg, 1.58 mmol),1-bromo-2-(2-bromoethoxy)ethane (XLV) (439.53 mg, 1.9 mmol) and K₂CO₃(654.8 mg, 4.74 mmol) in MeCN (8 mL) was heated to reflux for 24 h. Thereaction mixture was concentrated and the residue was taken into DCM,washed with water and brine. The organic layer was then separated anddried (MgSO₄) before concentration to dryness. The crude was dissolvedin EtOAc, sonicated and the solid was collected by filtration and driedunder high vacuo to obtain the desired producttrans-N-(6-bromo-3-isoquinolyl)-4-morpholino-cyclohexanecarboxamide(XLVI) (320 mg, 0.765 mmol, 48.4% yield) as an off-white solid. ESIMSfound for C₂₀H₂₄BrN₃O₂ m/z 418.1 (⁷⁹BrM+1).

Step 4

To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLVII) (62.5 mg, 0.300 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (9.76mg, 0.010 mmol) andtrans-N-(6-bromo-3-isoquinolyl)-4-morpholino-cyclohexanecarboxamide(XLVI) (100 mg, 0.240 mmol) in MeCN (1 mL) was added a 2 M aqueoussolution of K₂CO₃ (0.3 mL, 0.600 mmol). N₂ gas was bubbled into themixture for 10 min and then the solution was heated to 90° C. for 0.5 h.The organic layer was carefully separated, absorbed on silica gel andpurified by flash column chromatography (0→40% CHCl₃/10% 7N NH₃ in MeOH)followed by preparative TLC. The purified product was suspended inEtOAc, sonicated and the solid was collected by filtration and driedunder high vacuo to obtaintrans-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]-4-morpholino-cyclohexanecarboxamide(1064) (18 mg, 0.043 mmol, 17.9% yield) as an off-white solid. ¹H NMR(499 MHz, DMSO-d₆) δ ppm 1.16-1.27 (2H, m), 1.42-1.56 (2H, m), 1.91 (4H,br t, J=11.80 Hz), 2.17-2.27 (1H, m), 2.44-2.49 (4H, m), 2.53 (3H, s),3.26-3.30 (1H, m), 3.54-3.58 (4H, m), 7.78 (1H, s), 7.79-7.83 (1H, m),8.09 (2H, dd, J=4.80, 3.98 Hz), 8.50 (1H, s), 9.10 (1H, s), 10.51 (1H,s); ESIMS found for C₂₄H₂₈N₄O₃ m/z 421.2 (M+1).

Example 6

Preparation of trans-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide (1017) is depicted below inScheme 16.

Step 1

To a stirred solution of trans-4-amino-N-(6-bromo-3-isoquinolyl)cyclohexanecarboxamide (XLVIII) (3 g, 8.61 mmol) in MeOH (50 mL) wasadded formaldehyde (8.64 mL, 42.93 mmol). After 15 min, Na(OAc)₃BH (9.1g, 42.93 mmol) was added and the mixture was stirred at room temperaturefor 2 h. The solvents were removed in vacuo, the residue taken in water,basified with 1N NaOH solution and extracted with CHCl₃. The organiclayer was separated, washed with water and brine, and dried overanhydrous Na₂SO₄. The solvent was concentrated and the crude wassuspended in diethyl ether, sonicated and the solid was collected byfiltration and dried under high vacuo to obtain the desired producttrans-N-(6-bromo-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide(XLIX) (2.28 g, 6.06 mmol, 70.3% yield) as a beige solid. ESIMS foundfor C₁₈H₂₂BrN₃O m/z 376.1 (⁷⁹BrM+1).

Step 2

To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (L) (138.9 mg, 0.660 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (43.4 mg,0.050 mmol), a 2 M aqueous solution of K₂CO₃ (0.66 mL, 1.33 mmol) andtrans-N-(6-bromo-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide(XLIX) (200 mg, 0.530 mmol) in MeCN (2.5 mL). N₂ gas was bubbled intothe mixture for 10 min and then the solution was heated to 110° C. for30 min in a microwave. The organic layer was carefully separated,absorbed on silica gel and purified by column chromatography (0→50%CHCl₃/10% 7N NH₃ MeOH in CHCl₃). The pure fractions were combined,concentrated and the product was suspended in EtOAc, sonicated and thesolid was collected by filtration, washed with diethyl ether and driedunder high vacuo to obtaintrans-4-(dimethylamino)-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]cyclohexanecarboxamide(1017) (92 mg, 0.243 mmol, 45.7% yield) as a beige solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.14-1.23 (2H, m), 1.43-1.54 (2H, m), 1.83-1.95 (4H,m), 2.10-2.16 (1H, m), 2.18 (6H, s), 2.44-2.49 (1H, m), 2.53 (3H, s),7.78 (1H, s), 7.79-7.84 (1H, m), 8.06-8.13 (2H, m), 8.50 (1H, s), 9.10(1H, s), 10.49 (1H, s); ESIMS found for C₂₂H₂₆N₄O₂ m/z 379.2 (M+1).

Example 7

Preparation oftrans-4-((4-methylpiperazin-1-yl)methyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide (1007) is depicted below inScheme 17.

Step 1

To a mixture of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate(LI) (5.0 g, 29.03 mmol) imidazole (3.95 g, 58.07 mmol) andtert-butyl-chloro-dimethyl-silane (4.81 g, 31.94 mmol) in DMF (50 mL)was stirred at room temperature for 48 h. The solvents were concentratedto ½ volume, water (200 mL) was added and extracted with MTBE. Theorganic layer was separated and washed with 1 N HCl, H₂O and brine. Theorganics were dried over anhydrous Na₂SO₄ and the solvent wasconcentrated to dryness to obtain methyltrans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylate(LII) (8.09 g, 28.24 mmol, 97.3% yield) as a colorless oil. ESIMS foundfor C₁₅H₃₀O₃Si m/z 287.1 (M+1).

Step 2

To a stirred solution of methyltrans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylate(LII) (8.05 g, 28.1 mmol) in a mixture of THF (20 mL) and MeOH (20 mL)was added 2 M solution of NaOH (28.1 mL, 56.2 mmol). The mixture wasstirred at room temperature for 5 h. The solvent was reduced to ⅓volume, acidified with 1 N HCl and the resulting solid was filtered,washed with water and dried under high vacuo to obtain 5 grams of thedesired product. The filtrates were extracted with EtOAc (2×), washedwith water, brine, dried over anhydrous Na₂SO₄, concentrated, and driedin vacuo to obtain another 1.1 g oftrans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid(LIII) (Total 6.1 g, 22.39 mmol, 79.7% yield) as a white solid. ¹H NMR(499 MHz, DMSO-d₆) δ ppm 0.01 (6H, s), 0.83-0.87 (8H, m), 0.88-0.96 (2H,m), 1.19-1.32 (2H, m), 1.32-1.43 (1H, m), 1.74 (2H, br dd, J=13.31, 3.16Hz), 1.84-1.94 (2H, m), 2.09 (1H, tt, J=12.18, 3.46 Hz), 3.38 (2H, d,J=6.31 Hz), 11.98 (1H, br s); ESIMS found for C₁₄H₂₈O₃Si m/z 273.1(M+1).

Step 3

A mixture of DIPEA (5.86 mL, 33.62 mmol), DMAP (0.27 g, 2.24 mmol) andHATU (5.11 g, 13.45 mmol) in DMF (30 mL) was stirred for 10 min.6-Bromoisoquinolin-3-amine (XII) (2.5 g, 11.21 mmol) was then addedfollowed by the addition of trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (LIII) (3.66 g,13.45 mmol). The mixture was heated to 70° C. overnight. An additional0.5 equiv. of HATU were added and the mixture was continued foradditional 6 h. The solvent was concentrated, the residue taken up inEtOAc, washed with sat. NaHCO₃ and brine. The organic layer was thenconcentrated and the crude product was purified by column chromatography(0→30% EtOAc/hexanes). The pure fractions were combine and concentratedto obtaintrans-N-(6-bromo-3-isoquinolyl)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxamide(LIV) (2.25 g, 4.71 mmol, 42.0% yield) as a crystalline off-white solid.¹H NMR (499 MHz, DMSO-d₆) δ ppm 0.03 (6H, s), 0.87 (9H, s), 0.98 (2H,qd, J=12.72, 3.29 Hz), 1.38-1.51 (3H, m), 1.73-1.82 (2H, m), 1.85-1.92(2H, m), 2.46-2.55 (1H, m), 3.41 (2H, d, J=6.04 Hz), 7.62 (1H, dd,J=8.64, 1.78 Hz), 7.99 (1H, d, J=8.78 Hz), 8.16 (1H, d, J=1.65 Hz), 8.44(1H, s), 9.13 (1H, s), 10.53 (1H, s); ESIMS found for C₂₃H₃₃BrN₂O₂Si m/z477.2 (⁷⁹BrM+1).

Step 4

To a stirred solution of trans-N-(6-bromo-3-isoquinolyl)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxamide (LIV) (2.24 g, 4.69mmol) in THF (10 mL) was added 1 M solution of TBAF (7.04 mL, 7.04 mmol)in THF. The mixture was stirred at room temperature overnight (monitoredby LCMS). Water was added to the reaction mixture and extracted withEtOAc (2×). The organic layer was separated, washed with brine, anddried over anhydrous Na₂SO₄. The solvent was concentrated and the crudeproduct was suspended in EtOAc, sonicated and the solid was collected byfiltration and dried under high vacuo to obtaintrans-N-(6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide(LV) (1.437 g, 3.96 mmol, 84.3% yield) as a light beige solid. ESIMSfound for C₁₇H₁₉BrN₂O₂ m/z 363.1 (⁷⁹BrM+1).

Step 5

To a stirred solution of DMSO (0.59 mL, 8.26 mmol) in DCM (3 mL) at −78°C. was added dropwise under Ar, oxalyl dichloride (0.36 mL, 4.13 mmol)in DCM (1 mL). After 15 min,trans-N-(6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide(LV) (1.0 g, 2.75 mmol) in a mixture of THF (12 mL) and DMSO (0.5 mL)was added and the mixture was stirred at −78° C. for 1 h. Then, TEA(1.15 mL, 8.26 mmol) was added and the mixture was continued to stir for1 h and warmed to room temperature for 1 h. The reaction mixture wasdiluted with H₂O and DCM and the organic layer separated, washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to obtaintrans-4-formyl-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]cyclohexanecarboxamide(LVI) (215 mg, 0.593 mmol, 108.1% yield) as a white solid which was usedfor next step without further purification. ESIMS found for C₁₇H₁₇BrN₂O₂m/z 361.05 (⁷⁹BrM+1).

Step 6

To a mixture of 1-methylpiperazine (0.23 mL, 2.03 mmol),trans-N-(6-bromo-3-isoquinolyl)-4-formyl-cyclohexanecarboxamide (LVI)(490 mg, 1.36 mmol) and in DCE (6 mL) was stirred for 20 min. Then,Na(OAc)₃BH (431.2 mg, 2.03 mmol) was added and the mixture was stirredovernight at room temperature. The reaction mixture was diluted withDCM, washed with sat. NaHCO₃, H₂O and brine. The organic layer was thenseparated and dried (MgSO₄) before concentration to dryness to obtaintrans-N-(6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanecarboxamide(LVII) (610 mg, 1.37 mmol, 100% yield) as a beige solid. ESIMS found forC₂₂H₂₉BrN₄O m/z 445.1 (⁷⁹BrM+1).

Step 7

To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole(LVIII) (54.7 mg, 0.280 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (18.3 mg, 0.020mmol), andtrans-N-(6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanecarboxamide(LVII) (100 mg, 0.220 mmol) was taken in MeCN (1 mL) and was added a 2 Maqueous solution of K₂CO₃ (0.28 mL, 0.560 mmol). N₂ gas was bubbled intothe mixture for 10 min and then was heated to 110° C. for 0.5 h. Theorganic layer was separated, absorbed on silica gel and was purified bycolumn chromatography (10→80% CHCL₃/10% 7N NH₃ MeOH in CHCl₃). The purefractions were combined, concentrated, the residue suspended in amixture EtOAc/diethyl ether, sonicated and the resulting solid wascollected by filtration and dried under vacuo to obtaintrans-4-[(4-methylpiperazin-1-yl)methyl]-N-(6-oxazol-5-yl-3-isoquinolyl)cyclohexanecarboxamide(1007) (25 mg, 0.058 mmol, 25.7% yield) as a light brown solid. ¹H NMR(499 MHz, DMSO-d₆) δ ppm 0.83-0.96 (2H, m), 1.41-1.54 (3H, m), 1.79-1.92(4H, m), 2.08 (2H, d, J=7.41 Hz), 2.14 (3H, s), 2.31 (8H, br s),2.52-2.56 (1H, m), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s), 8.12(1H, d, J=8.51 Hz), 8.18 (1H, s), 8.53 (1H, s), 8.57 (1H, s), 9.12 (1H,s), 10.50 (1H, s); ESIMS found for C₂₅H₃₁N₅O₂ m/z 434.2 (M+1).

Example 8

Preparation of1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide(822) is depicted below in Scheme 18.

Steps 1-2

To a mixture of 6-bromoisoquinolin-3-amine (XII) (4.0 g, 17.93 mmol),Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.03 g, 1.26 mmol), KOAc (4.39 g, 44.83 mmol)and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.01 g, 19.72 mmol) in 1,4-dioxane (50 mL) was bubbled with N₂ for 2min. The reaction mixture was sealed and heated at 90° C. for 1.5 h. Thereaction was cooled to room temperature, filtered and washed with EtOAc.The filtrate was concentrated and the residue taken in dioxane (50 mL).To the suspension was added 4-bromo-2-methyl-pyrazole-3-carbaldehyde(LX) (3.39 g, 17.93 mmol) followed by K₃PO₄ (9.52 g, 44.83 mmol),Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.03 g, 1.26 mmol) and water (15 mL). Themixture was purged with N₂ for a min, sealed and heated again at 90° C.for 19 h. The mixture was cooled to room temperature and concentrated toabout 20 mL. The concentrate was diluted with EtOAc and filtered througha pad of Celite. The filtrate was diluted with water and the organiclayer separated. The organic layer was washed with brine; dried,filtered and concentrated. The residue was triturated in ether and theresulting solid filtered to afford4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (4.1 g,16.2 mmol, 90.6% yield) as a brown solid. ¹H NMR (499 MHz, DMSO-d₆) δppm 0.01 (6H, s), 0.86 (9H, s), 0.88-1.00 (2H, m), 1.23-1.35 (2H, m),1.35-1.46 (1H, m), 1.69-1.79 (2H, m), 1.85-1.95 (2H, m), 2.21 (1H, tt,J=12.21, 3.57 Hz), 3.38 (2H, d, J=6.31 Hz), 3.57 (3H, s) ESIMS found forC₁₄H₁₂N₄O m/z 252.95 (M+1).

Step 3

To a mixture of4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (1.07g, 4.25 mmol), piperidine (0.84 mL, 8.51 mmol) and catalytic HOAc in DCE(10 mL) was stirred for 30 min. Na(OAc)₃BH (1.8 g, 8.51 mmol) was addedand stirring was continued for 12 h at room temperature. The reactionmixture was quenched with minimum amount of aq. saturated ammoniumchloride solution, and concentrated under vacuum. The residue wasadsorbed on silica gel and purified by chromatography (0→20% 7NNH₃-MeOH/CHCl₃) to obtain6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine (LXII)(800 mg, 2.49 mmol, 58.5% yield) as a white solid. ESIMS found forC₁₉H₂₃N₅ m/z 322.2 (M+1).

Step 4

To a mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid(XXVIII) (1.15 mL, 1.63 mmol), HATU (703.87 mg, 1.85 mmol) and DIPEA(0.57 mL, 3.27 mmol) in DMF (5 mL) was stirred for 10 min. To thismixture was added 6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine (LXII) (350 mg, 1.09 mmol) and DMAP(26.61 mg, 0.220 mmol) and the mixture was stirred at 50° C. overnight.The solvent was concentrated and the residue was taken up in EtOAc,washed with sat. NaHCO₃, water and brine. The organic layer was thenseparated and dried (MgSO₄) before concentrating to dryness. The crudeproduct was purified by column chromatography (25%→100% EtOAc/hexanes).The pure fractions were combined, concentrated, the residue trituratedwith diethyl ether, sonicated and the solid were collected by filtrationand dried under high vacuo to obtain tert-butyl4-[[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (LXIII)(550 mg, 1.03 mmol, 94.8% yield) as a dark beige solid. ESIMS found forC₃₀H₄₀N₆O₃ m/z 533.3 (M+1).

Step 5

To a stirred solution of tert-butyl4-[[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (LXIII)(300 mg, 0.560 mmol) in DCM (5 mL) was added TFA (1.23 mL, 15.91 mmol).The mixture was stirred overnight at room temperature. The solvent wasevaporated and the residue was adsorbed on silica gel, purified bycolumn chromatography (0-10% 7N.NH₄-MeOH/CHCl₃), pure fractions wereconcentrated and the solid were triturated with MeOH, filtered and driedto obtain N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide (LXIV) (191 mg,0.441 mmol, 78.4% yield) as a white solid. ESIMS found for C₂₅H₃₂N₆O m/z433.3 (M+1).

Step 6

To stirred mixture ofN-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide(LXIV) (95 mg, 0.220 mmol) and 2-methylpropanal (0.06 mL, 0.660 mmol) inMeOH (2 mL) was added NaCNBH₃ (27.6 mg, 0.440 mmol) at 0° C. The mixturewas stirred for 30 min-1 h at room temperature. Reaction mixture wasquenched with minimum amount of aq. saturated ammonium chloridesolution, concentrated under vacuum and the residue was adsorbed onsilica gel, purified by chromatography (0→10% 7N.NH3-MeOH/CHCl₃) toobtain1-isobutyl-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide(822) (30 mg, 0.061 mmol, 28.0% yield) as a beige solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.33-1.42 (2H, m),1.45-1.53 (4H, m), 1.61-1.72 (2H, m), 1.72-1.81 (3H, m), 1.86 (2H, td,J=11.60, 1.78 Hz), 2.02 (2H, d, J=7.41 Hz), 2.36 (4H, br s), 2.52-2.59(1H, m), 2.86 (2H, br d, J=11.53 Hz), 3.65 (2H, s), 3.91 (3H, s), 7.68(1H, dd, J=8.37, 1.51 Hz), 7.79 (1H, s), 8.02 (1H, d, J=9.33 Hz), 8.03(1H, s), 8.46 (1H, s), 9.07 (1H, s), 10.46 (1H, s); ESIMS found forC₂₉H₄₀N₆O m/z 489.3 (M+1).

Example 9

Preparation of2-[(3R)-3-fluoropyrrolidin-1-yl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide(274) is depicted below in Scheme 19.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (1.0 g, 4.48mmol) and DMAP (109.5 mg, 0.90 mmol) in DCE (35 mL) was added DIPEA(3.12 mL, 17.93 mmol) followed by the addition of 2-chloroacetylchloride (1.07 mL, 13.45 mmol). The mixture was heated to 75° C.overnight. The reaction mixture was then cooled to room temperature,diluted with DCM, washed with H₂O and brine, the organic layer were thenseparated and dried over MgSO₄ before concentrating to dryness. Thecrude product was then purified by flash column chromatography usingEtOAc/hexanes (0→100%) to obtainN-(6-bromo-3-isoquinolyl)-2-chloro-acetamide (LXV) as a light yellowsolid (350 mg, 1.16 mmol, 26.1% yield). ESIMS found for C₁₁H₈BrClN₂O m/z298.9 (⁷⁹BrM+H).

Step 2

To a solution of N-(6-bromo-3-isoquinolyl)-2-chloro-acetamide (LXV) (100mg, 0.33 mmol), (3R)-3-fluoropyrrolidine hydrochloride (LXVI) (209.6 mg,1.67 mmol), KI (0.02 mL, 0.33 mmol) and K₂CO₃ (461.4 mg, 3.34 mmol) inDMF (2 mL) was heated to 90° C. overnight. The reaction was thenconcentrated to dryness and the residue was taken up in EtOAc and theorganic layer was washed with water then brine. The organic layer wasthen separated and dried over MgSO₄ before concentration to dryness toobtainN-(6-bromo-3-isoquinolyl)-2-[(3R)-3-fluoropyrrolidin-1-yl]acetamide(LXVII) as a dark brown thick gum (110 mg, 0.312 mmol, 94.6% yield).Used for next step without purification. ESIMS found for C₁₅H₁₅BrFN₃Om/z 352.2 (⁷⁹BrM+H).

Step 3

To a solution ofN-(6-bromo-3-isoquinolyl)-2-[(3R)-3-fluoropyrrolidin-1-yl]acetamide(LXVII) (116.2 mg, 0.33 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo(LXVIII) (103 mg, 0.50 mmol), Pd(dppf)Cl₂ (27 mg, 0.03 mmol) in MeCN(1.5 mL) was added a 2 M aqueous solution of K₂CO₃ (0.5 mL, 0.99 mmol).N₂ gas was bubbled into the mixture for 10 min and then heated to 80° C.for 3 h. The organic layer was carefully separated, absorbed on silicagel and purified by flash column chromatography (0→30% CHCl₃/10% 7 N NH₃in MeOH). The pure fractions were concentrated, the residue suspended inminimum EtOAc, sonicated and the resulting solid was collected byfiltration, washed with diethyl ether and dried to obtain2-[(3R)-3-fluoropyrrolidin-1-yl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide(274) as a white solid (58.0 mg, 0.164 mmol, 49.7% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 1.88-2.03 (m, 1H), 2.12-2.28 (m, 1H), 2.53-2.61(m, 1H), 2.86 (ddd, J=32.40, 11.80, 4.95 Hz, 1H), 2.95-3.04 (m, 2H),3.41 (s, 2H), 3.90 (s, 3H), 5.26 (ddd, J=55.80, 6.05, 4.95 Hz, 1H), 7.77(dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (s, 2H), 8.37(s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 10.02 (s, 1H); ESIMS found forC₁₉H₂₀FN₅O m/z 354.1 (M+1).

Example 10

Preparation of(S)—N-(6-(1-(methyl-d₃)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide(971) is depicted below in Scheme 20.

Step 1

To a stirred suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (LXIX)(1.435 g, 7.4 mmol) and Cs₂CO₃ (2.89 g, 8.87 mmol) in DMF (15 mL) wasadded trideuterio(iodo)methane (0.51 mL, 8.13 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture was filteredand the filtrates were concentrated and dried under high vacuo to obtain4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole(LXX) (3.9 g, 18.48 mmol, 249.8% yield) as a white solid which was usedfor next step without purification. ESIMS found for C₁₀H₁₄[²H₃]BN₂O₂ m/z212. (M+1).

Step 2

To a mixture of 6-bromo-3-chloro-isoquinoline (XII) (0.5 g, 2.06 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole(LXX) (1.305 g, 6.19 mmol) and SPhos Pd G4 (81.9 mg, 0.100 mmol) in1,4-dioxane (10 mL) and was added a 2 M aqueous solution of K₂CO₃ (3.88mL, 7.77 mmol). N₂ gas was bubbled into the mixture for 10 min and thenthe mixture was heated to 110° C. for 0.5 h in a microwave. The organiclayer was carefully separated, absorbed on silica gel and purified bycolumn chromatography (0→100% hexanes/EtOAc) to obtain3-chloro-6-[1-(trideuteriomethyl)pyrazol-4-yl]isoquinoline (LXXI) (400mg, 1.62 mmol, 78.6% yield) as an off-white solid. ESIMS found forC₁₃H₇[²H₃]ClN₃ m/z 246.9 (M+1).

Step 3

To a mixture of (S)-2-aminopropanamide HCl (LXXII) (100 mg, 0.330 mmol),1,4-dibromobutane (LXXIII) (1.9 mL, 16.06 mmol), K₂CO₃ (4.437 g, 32.11mmol) and KI (266.5 mg, 1.61 mmol) in MeCN (80 mL) was heated to refluxfor 40 h. 1 N hydrochloric acid (100 mL) and DCM (100 mL) were added tothe reaction mixture. The organic phase is separated off and discarded.The aqueous phase is made basic with a NaOH solution and extracted withCHCl₃ (3×80 ml). The organic layers were combined and dried under highvacuo to obtain (2S)-2-pyrrolidin-1-ylpropanamide (LXXIV) (1.10 g, 7.45mmol, 46.4% yield) as a white solid which was used for next step withoutpurification. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.15 (3H, d, J=6.86 Hz),1.63-1.72 (4H, m), 2.44-2.49 (4H, m), 2.72 (1H, q, J=6.68 Hz), 6.88 (1H,br s), 7.07 (1H, br s) ESIMS found for C₇H₁₄N₂O m/z 143.1 (M+1).

Step 4

To a mixture of (2S)-2-pyrrolidin-1-ylpropanamide (LXXIV) (420.1 mg,2.95 mmol) BrettPhos Pd G3 (223.2 mg, 0.250 mmol),3-chloro-6-[1-(trideuteriomethyl)pyrazol-4-yl]isoquinoline (LXXI) (200mg, 0.810 mmol) and K₃PO₄ (1.045 g, 4.92 mmol) was taken in 1,4-dioxane(5 mL). N₂ gas was bubbled into the mixture for 10 min and then themixture was heated to 100° C. for 16 h. The reaction mixture wasfiltered through Celite, washed with EtOAc, the filtrates concentratedand the crude product was purified by flash chromatography followed bypreparative TLC (50% CHCl₃/10% 7N NH₃ in MeOH) to obtain(2S)-2-pyrrolidin-1-yl-N-[6-[1-(trideuteriomethyl)pyrazol-4-yl]-3-isoquinolyl]propanamide(971) (150.0 mg, 0.426 mmol, 50.6% yield) as a beige solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.75 (4H, br s), 2.59-2.69(4H, m), 3.29-3.32 (1H, m), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d,J=8.51 Hz), 8.08 (2H, s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.91(1H, s); ESIMS found for C₂₀H₂₀[²H₃]N₅O m/z 353.0 (M+1).

Example 11

Preparation ofN-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-(1-piperidyl) acetamide(275) is depicted below in Scheme 21.

Step 1

To a stirred mixture ofN-(6-bromo-3-isoquinolyl)-2-(1-piperidyl)acetamide (LXXV) (100 mg, 0.29mmol) tributyl-(3-methylimidazol-4-yl)stannane (LXXVI) (117.24 mg, 0.32mmol) Pd(PPh₃)₄ (33.2 mg, 0.03 mmol) and cuprous iodide (5.47 mg, 0.03mmol) in DMF (2 mL) was bubbled N₂ gas for 10 min and then heated to 90°C. overnight. The reaction mixture was concentrated, absorbed on silicagel and purified by flash column chromatography using CHCl₃/10% 7 N NH₃in MeOH (0→40%). The pure fractions were concentrated, the residuesuspended in diethyl ether, sonicated and the resulting solids werecollected by filtration, and dried to obtainN-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-(1-piperidyl)acetamide(275) as a white solid (53.0 mg, 0.152 mmol, 52.3% yield). ¹H NMR(DMSO-d₆, 500 MHz) δ ppm 1.43 (br d, J=4.94 Hz, 2H), 1.59 (quin, J=5.63Hz, 4H), 2.52 (br d, J=5.21 Hz, 4H), 3.18 (s, 2H), 3.84 (s, 3H), 7.33(br s, 1H), 7.70 (dd, J=8.51, 1.65 Hz, 1H), 7.81 (br s, 1H), 8.06 (s,1H), 8.11 (d, J=8.51 Hz, 1H), 8.53 (s, 1H), 9.14 (s, 1H), 9.98 (s, 1H);ESIMS found for C₂₀H₂₃N₅O m/z 350.2 (M+1).

Example 12

Preparation of1-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea(1037) is depicted below in Scheme 22.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (200 mg,0.900 mmol), DMAP (11 mg, 0.090 mmol) and TEA (0.5 mL, 3.59 mmol) in THF(40 ml) was added trichloromethyl carbonochloridate (0.11 mL, 0.900mmol) and the mixture was stirred for 1 h at room temperature.N,1-dimethylpiperidin-4-amine (LXXVII) (115 mg, 0.900 mmol) was thenadded and the mixture was stirred for 2 h at room temperature. Thereaction was concentrated and the residue taken in DCM, washed withwater, sat.NaHCO₃ and brine. The organic layer was dried over anhydrousNa₂SO₄, solvents removed in vacuo and the crude was purified by columnchromatography (0→10% CHCl₃/7N NH₃ in MeOH) to obtain3-(6-bromo-3-isoquinolyl)-1-methyl-1-(1-methyl-4-piperidyl)urea(LXXVIII) (98 mg, 0.260 mmol, 29.0% yield) as a beige solid. ESIMS foundfor C₁₇H₂₁BrN₄O m/z 377.1 (⁷⁹BrM+H).

Step 2

To a mixture of Pd(dppf)Cl₂—CH₂Cl₂ adduct (19.6 mg, 0.020 mmol),1-(6-bromo-3-isoquinolyl)-3-(1-methyl-4-piperidyl)urea (LXXVIII) (87 mg,0.240 mmol), and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(LXVIII) (59.8 mg, 0.290 mmol) in MeCN (5 mL) was added a 2 M aqueoussolution of K₂CO₃ (0.24 mL, 0.480 mmol). N₂ gas was bubbled into themixture for 10 min and then heated at 110° C. for 30 min in a microwave.The organic layer was carefully separated, absorbed on silica gel andpurified by flash column chromatography (0→10% 7N NH₃ in MeOH/CHCl₃).The pure fractions were combined, concentrated and the residue wastriturated from DCM/hexanes. The solid was collected by filtration anddried under high vacuum to obtain1-(1-methyl-4-piperidyl)-3-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]urea(1037) (35 mg, 0.096 mmol, 40.1% yield) as a beige solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.52 (2H, br d, J=10.15 Hz), 1.74 (2H, qd, J=12.12,3.70 Hz), 1.93-2.02 (2H, m), 2.17 (3H, s), 2.82 (2H, br d, J=11.25 Hz),2.88 (3H, s), 3.90 (3H, s), 4.09 (1H, tt, J=12.01, 3.91 Hz), 7.65-7.72(1H, m), 7.93-7.99 (2H, m), 8.06 (1H, s), 8.15 (1H, s), 8.33 (1H, s),8.76 (1H, s), 8.97 (1H, s); ESIMS found for C₂₁H₂₆N₆O m/z 379.2 (M+1).

The following compounds were prepared in accordance with the proceduresdescribed in the above Examples 1-12.

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide1

Beige solid (32.0 mg, 0.109 mmol, 31.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.77-0.90 (m, 4H), 2.03-2.12 (m, 1H), 3.90 (s, 3H), 7.74 (dd,J=8.51, 1.65 Hz, 1 H), 7.96-8.03 (m, 2H), 8.08 (s, 1H), 8.35 (s, 1H),8.40 (s, 1H), 9.03 (s, 1H), 10.83 (s, 1H); ESIMS found for C₁₇H₁₆N₄O m/z293.1 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexanecarboxamide 3

Beige solid (41.6 mg, 0.112 mmol, 56.2% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.66-1.90 (m, 4H), 1.91-2.00 (m, 2H), 2.06-2.18 (m, 2H),2.66-2.76 (m, 1H), 3.90 (s, 3H), 7.75 (dd, J=8.64, 1.51 Hz, 1H), 8.00(d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.43 (s,1H), 9.03 (s, 1H), 10.57 (s, 1H); ESIMS found for C₂₀H₂₀F₂N₄O m/z 371.2(M+1).

trans-4-Methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 4

White solid (101 mg, 0.277 mmol, 62.2% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.07-1.17 (2H, m), 1.43-1.56 (2H, m), 1.84-1.95 (2H, m), 2.03-2.11(2H, m), 2.51-2.57 (1H, m), 3.12 (1H, tt, J=10.67, 4.15 Hz), 3.25 (3H,s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.42 (1H, s), 9.02 (1H,s), 10.42 (1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide6

White solid (36 mg, 0.086 mmol, 30.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.15-1.30 (2H, m), 1.41-1.56 (2H, m), 1.91 (4H, brt, J=11.11 Hz),2.17-2.28 (1H, m), 3.28 (4H, br s), 3.50-3.60 (4H, m), 3.90 (3H, s),7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s),8.07 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s);ESIMS found for C₂₄H₂₉N₅O₂ m/z 420.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 10

White solid (42.0 mg, 0.100 mmol, 36.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.91 (2H, qd, J=12.67, 3.16 Hz), 1.20-1.33 (1H, m),1.37-1.51 (2H, m), 1.51-1.61 (1H, m), 1.75-1.90 (4H, m), 2.29 (2H, d,J=6.86 Hz), 2.96-3.08 (2H, m), 3.48-3.60 (2H, m), 3.90 (3H, s),5.02-5.22 (1H, m), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.42 (1H, s), 9.01 (1H,s), 10.38 (1H, s); ESIMS found for C₂₄H₂₈FN₅O m/z 422.0 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide14

White solid (35.0 mg, 0.078 mmol, 28.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.82-0.95 (2H, m), 1.40-1.54 (4H, m), 1.79-1.91 (4H, m),2.08 (2H, d, J=7.14 Hz), 2.14 (3H, s), 2.23-2.41 (8H, m), 3.90 (3H, s),7.73 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s),8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.01 (1H, s), 10.37 (1H, s);ESIMS found for C₂₆H₃₄N₆O m/z 447.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide16

Yellow solid (10.8 mg, 0.035 mmol, 62.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 3.50 (br s, 2H), 3.76 (br s, 3H), 3.90 (s, 3H), 7.75 (dd,J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.06 (s, 1H), 8.09 (s,1H), 8.36 (s, 1H), 8.47 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMSfound for C₁₇H₁₇N₅O m/z 308.1 (M+1).

(S)-2-(3-Fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 69

Off-white solid (70.0 mg, 0.198 mmol, 41.0% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.87-2.04 (m, 1H), 2.12-2.29 (m, 1H), 2.55-2.62 (m, 1H),2.81-2.94 (m, 1H), 2.96-3.06 (m, 2H), 3.42 (s, 2H), 5.17-5.35 (m, 1H),7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (d, J=0.82Hz, 2H), 8.36 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 10.02 (s, 1H); ESIMSfound for C₁₉H₂₀FN₅O m/z 354.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide71

Off-white solid (30.0 mg, 0.093 mmol, 59.8% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.83-1.96 (m, 2H), 1.97-2.07 (m, 1H), 2.19-2.30 (m, 1H),3.83-3.88 (m, 1H), 3.90 (s, 3H), 3.99-4.07 (m, 1H), 4.53 (dd, J=8.23,5.76 Hz, 1H), 7.78 (dd, J=8.51, 1.65 Hz, 1H), 8.03 (d, J=8.51 Hz, 1H),8.10 (s, 2H), 8.37 (s, 1H), 8.42 (s, 1H), 9.05 (s, 1H), 9.75 (s, 1H);ESIMS found for C₁₈H₁₈N₄O₂ m/z 323.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide72

White solid (75.0 mg, 0.224 mmol, 92.2% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.65 (qd, J=12.30, 3.70 Hz, 2H), 1.81 (br d, J=10.70 Hz, 2H),2.64 (td, J=12.28, 2.33 Hz, 2H), 2.71 (ddt, J=11.32, 7.62, 3.84, 3.84Hz, 1H), 3.12 (br d, J=12.35 Hz, 2H), 3.90 (s, 3H), 7.75 (dd, J=8.51,1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35(s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 10.50 (s, 1H); ESIMS found forC₁₉H₂₁N₅O m/z 336.1 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide73

White solid (114.0 mg, 0.326 mmol, 42.1% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.60-1.73 (m, 2H), 1.73-1.80 (m, 2H), 1.86 (td, J=11.66, 2.20Hz, 2H), 2.16 (s, 3H), 2.45-2.55 (m, 1H), 2.81 (br d, J=11.53 Hz, 2H),3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H),8.02 (s, 1H), 8.07 (s, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.02 (s, 1H),10.46 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.2 (M+1).

1-Isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide75

Off-white solid (43.0 mg, 0.114 mmol, 40.22% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 0.97 (d, J=6.31 Hz, 6H), 1.63 (qd, J=11.98, 3.57 Hz, 2H),1.78 (br d, J=10.15 Hz, 2H), 2.11 (br t, J=11.11 Hz, 2H), 2.45-2.55 (m,1H), 2.62-2.73 (m, 1H), 2.83 (br d, J=10.98 Hz, 2H), 3.90 (s, 3H), 7.74(dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08(d, J=0.82 Hz, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.44 (s,1H); ESIMS found for C₂₂H₂₇N₅O m/z 378.3 (M+1).

1-Cyclopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide76

White solid (42.0 mg, 0.112 mmol, 24.6% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.25-0.33 (m, 2H), 0.38-0.46 (m, 2H), 1.53-1.65 (m, 3H), 1.76(br d, J=10.98 Hz, 2H), 2.11-2.22 (m, 2H), 2.51-2.60 (m, 1H), 2.98 (brd, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99(d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s,1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C₂₂H₂₅N₅O m/z 376.2(M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide77

White solid (128.0 mg, 0.327 mmol, 60.3% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.85 (d, J=6.59 Hz, 6H), 1.60-1.73 (m, 2H), 1.73-1.80 (m,3H), 1.82-1.90 (m, 2H), 2.01 (d, J=7.41 Hz, 2H), 2.51-2.57 (m, 1H), 2.86(br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.37 Hz, 1H),7.99 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44(s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C₂₃H₂₉N₅O m/z392.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide78

White solid (16.5 mg, 0.041 mmol, 13.7% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.85 (s, 9H), 1.67-1.76 (m, 4H), 2.04 (s, 2H), 2.16-2.26 (m,2H), 2.81 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s,1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found forC₂₄H₃₁N₅O m/z 406.3 (M+1).

1-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 81

White solid (257.0 mg, 0.674 mmol, 62.1% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2H), 1.75-1.83 (m, 2H), 2.03 (td,J=11.66, 2.20 Hz, 2H), 2.51-2.56 (m, 1H), 2.61 (dt, J=28.30, 4.90 Hz,2H), 2.91-2.99 (m, 2H), 3.90 (s, 3H), 4.53 (dt, J=47.75, 4.95 Hz, 2H),7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H),8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H);ESIMS found for C₂₁H₂₄FN₅O m/z 382.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 82

White solid (137.0 mg, 0.318 mmol, 54.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.58-1.74 (m, 2H), 1.79 (br d, J=10.70 Hz, 2H), 1.92-2.02 (m,2H), 2.40-2.60 (m, 5H), 2.93 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74(dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08(s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.48 (s, 1H); ESIMSfound for C₂₂H₂₄F₃N₅O m/z 432.2 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 83

Off-white solid (29.0 mg, 0.070 mmol, 23.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.62 (t, J=19.21 Hz, 3H), 1.66-1.73 (m, 2H), 1.73-1.81 (m,2H), 2.21 (td, J=11.66, 2.47 Hz, 2H), 2.50-2.57 (m, 1H), 2.70 (t,J=14.00 Hz, 2H), 2.94 (br d, J=11.53 Hz, 2H), 3.89 (s, 3H), 7.74 (dd,J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (d,J=0.82 Hz, 1H), 8.34 (s, 1H), 8.43 (s, 1H), 9.01 (s, 1H), 10.48 (s, 1H);ESIMS found for C₂₂H₂₅F₂N₅O m/z 414.2 (M+1).

1-(2,2-Difluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 84

White solid (147.0 mg, 0.368 mmol, 7.71% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2H), 1.74-1.83 (m, 2H), 2.14-2.23(m, 2H), 2.52-2.59 (m, 1H), 2.72 (td, J=15.57, 4.25 Hz, 2H), 2.96 (br d,J=11.53 Hz, 2H), 3.90 (s, 3H), 6.13 (tt, J=55.75, 4.15 Hz, 1H), 7.74(dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07(s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMSfound for C₂₁H₂₃F₂N₅O m/z 400.2 (M+1).

1-(2-Fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide85

Off-white solid (110.0 mg, 0.269 mmol, 47.4% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 1.31 (d, J=21.45 Hz, 6H), 1.64-1.81 (m, 4H), 2.10 (td,J=11.53, 2.74 Hz, 2H), 2.45 (t, J=22.85 Hz, 2H), 2.51-2.57 (m, 1H), 2.95(br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.37 Hz, 1H),8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44(s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C₂₃H₂₈FN₅O m/z410.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide 87

White solid (58.0 mg, 0.138 mmol, 57.8% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.31 (s, 3H), 1.59-1.70 (m, 2H), 1.71-1.79 (m, 2H), 1.97 (td,J=11.53, 2.47 Hz, 2H), 2.48 (s, 2H), 2.51-2.57 (m, 1H), 2.62 (br d,J=11.25 Hz, 2H), 3.90 (s, 3H), 4.19 (d, J=5.49 Hz, 2H), 4.36 (d, J=5.76Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04(s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47(s, 1H); ESIMS found for C₂₄H₂₉N₅O₂ m/z 420.3 (M+1).

1-(2-Methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 89

White solid (32.0 mg, 0.081 mmol, 28.7% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.59-1.71 (m, 2H), 1.73-1.81 (m, 2H), 1.92-2.04 (m, 2H), 2.46(t, J=5.90 Hz, 2H), 2.51-2.58 (m, 1H), 2.92 (br d, J=11.25 Hz, 2H), 3.24(s, 3H), 3.43 (t, J=6.04 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (d, J=0.82 Hz, 1H),8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found forC₂₂H₂₇N₅O₂ m/z 394.2 (M+1).

1-(2-Isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 90

Off-white solid (71.0 mg, 0.168 mmol, 56.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.08 (d, J=6.04 Hz, 7H), 1.59-1.71 (m, 2H), 1.73-1.82 (m,2H), 1.98 (td, J=11.60, 2.06 Hz, 2H), 2.44 (t, J=6.17 Hz, 2H), 2.51-2.58(m, 1H), 2.92 (br d, J=11.53 Hz, 2H), 3.46 (t, J=6.31 Hz, 2H), 3.53 (dt,J=12.14, 6.14 Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.64, 1.51 Hz, 1H),7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44(s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found for C₂₄H₃₁N₅O₂ m/z422.2 (M+1).

4-Fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide91

White solid (54.0 mg, 0.153 mmol). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm1.79-1.90 (m, 2H), 1.93-2.12 (m, 2H), 2.74 (td, J=12.28, 2.33 Hz, 2H),2.86-2.94 (m, 2H), 3.90 (s, 3H), 7.81 (dd, J=8.64, 1.51 Hz, 1H), 8.05(d, J=8.51 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.36 (s, 1H), 8.40 (s,1H), 9.08 (s, 1H), 9.78 (d, J=4.39 Hz, 1H); ESIMS found for C₁₉H₂₀FN₅Om/z 354.2 (M+1).

4-Fluoro-1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 92

White solid (57.0 mg, 0.155 mmol, 68.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.89-2.01 (m, 2H), 2.05-2.20 (m, 4H), 2.22 (s, 3H), 2.69-2.77(m, 2H), 3.91 (s, 3H), 7.81 (dd, J=8.51, 1.37 Hz, 1H), 8.05 (d, J=8.78Hz, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.36 (s, 1H), 8.40 (s, 1H), 9.08(s, 1H), 9.87 (d, J=4.12 Hz, 1H); ESIMS found for C₂₀H₂₂FN₅O m/z 368.2(M+1).

4-Fluoro-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 96

White solid (37.0 mg, 0.090 mmol, 39.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.74-1.85 (m, 1H), 1.91-2.01 (m,2H), 2.09 (d, J=7.41 Hz, 2H), 2.11-2.21 (m, 4H), 2.78 (br d, J=8.23 Hz,2H), 3.90 (s, 3H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.05 (d, J=8.51 Hz,1H), 8.10 (s, 1H), 8.12 (s, 1H), 8.37 (s, 1H), 8.40 (s, 1H), 9.08 (s,1H), 9.86 (d, J=4.39 Hz, 1H); ESIMS found for C₂₃H₂₈FN₅O m/z 410.2(M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide110

White solid (37.7 mg, 0.112 mmol, 47.0% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.34-1.48 (m, 1H), 1.55-1.64 (m, 1H), 1.64-1.73 (m, 1H),1.81-1.92 (m, 1H), 2.52-2.67 (m, 2H), 2.71-2.85 (m, 2H), 2.98 (dd,J=11.94, 3.16 Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H),8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.42(s, 1H), 9.01 (s, 1H), 10.75 (s, 1H); ESIMS found for C₁₉H₂₁N₅O m/z336.1 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide111

White solid (6.5 mg, 0.019 mmol, 44.8% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 1.33-1.49 (m, 1H), 1.55-1.64 (m, 1H), 1.64-1.74 (m, 1H), 1.81-1.93(m, 1H), 2.52-2.66 (m, 2H), 2.71-2.86 (m, 2H), 2.98 (dd, J=11.80, 2.74Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.64, 1.51 Hz, 1H), 8.00 (d, J=8.51Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.01(s, 1H), 10.75 (s, 1H); ESIMS found for C₁₉H₂₁N₅O m/z 336.2 (M+1).

(S)-1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide112

Beige solid (17.8 mg, 0.045 mmol, 4.7% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 0.88 (d, J=6.59 Hz, 3H), 0.90 (d, J=6.59 Hz, 3H), 1.48-1.60 (m,2H), 1.64-1.73 (m, 1H), 1.77-1.86 (m, 2H), 2.07 (d, J=7.41 Hz, 2H), 2.10(br dd, J=4.25, 3.16 Hz, 1H), 2.30 (br d, J=7.14 Hz, 1H), 2.55-2.63 (m,1H), 2.76 (br d, J=7.68 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s,1H), 8.42 (s, 1H), 9.01 (s, 1H), 10.68 (s, 1H); ESIMS found forC₂₃H₂₉N₅O m/z 392.2 (M+1).

(R)-1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide113

Beige solid (110 mg, 0.281 mmol, 26.8% yield). ¹H NMR (DMSO-d₆, 500 MHz)δ ppm 0.88 (3H, d, J=6.59 Hz), 0.90 (3H, d, J=6.59 Hz), 1.49-1.59 (2H,m), 1.68 (1H, br dd, J=8.23, 3.29 Hz), 1.76-1.88 (2H, m), 2.07 (2H, d,J=7.41 Hz), 2.10 (1H, br s), 2.30 (1H, br d, J=6.59 Hz), 2.55-2.62 (1H,m), 2.76 (2H, br d, J=7.68 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s),8.42 (1H, s), 9.01 (1H, s), 10.68 (1H, s); ESIMS found for C₂₃H₂₉N₅O m/z392.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide114

White solid (95.0 mg, 0.282 mmol, 63.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.80 (m, 4H), 2.76-2.87 (m, 1H), 3.32-3.38 (m, 2H),3.90 (s, 3H), 3.91-3.95 (m, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00(d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s,1H), 9.03 (s, 1H), 10.49 (s, 1H); ESIMS found for C₁₉H₂₀N₄O₂ m/z 337.15(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 115

Off-white solid (23.0 mg, 0.066 mmol, 16.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.43 (2H, br d, J=4.39 Hz), 1.59 (4H, quin, J=5.56 Hz), 2.52(4H, br s), 3.17 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz),8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04(1H, s), 9.91 (1H, s); ESIMS found for C₂₀H₂₃N₅O m/z 350.2 (M+1).

2-(4-Fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide116

Off-white solid (80.0 mg, 0.218 mmol, 44.3% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.73-1.86 (2H, m), 1.87-2.01 (2H, m), 2.54 (2H, ddd, J=11.39,7.41, 3.70 Hz), 2.67-2.76 (2H, m), 3.24 (2H, s), 4.66-4.83 (1H, m), 7.77(1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36(1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.98 (1H, s); ESIMS found forC₂₀H₂₂FN₅O m/z 368.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide118

Beige solid (18.0 mg, 0.049 mmol, 59.8% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 2.19 (3H, s), 2.33-2.46 (4H, m), 2.58 (4H, br s), 3.22 (2H,s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.93 (1H,s); ESIMS found for C₂₀H₂₄N₆O m/z 365.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide 119

Beige solid (70.0 mg, 0.228 mmol, 28.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.78-0.91 (4H, m), 2.02-2.13 (1H, m), 2.39 (3H, s), 3.65 (3H,s), 7.11 (1H, s), 7.59 (1H, dd, J=8.51, 1.37 Hz), 7.88 (1H, s), 8.07(1H, d, J=8.51 Hz), 8.49 (1H, s), 9.12 (1H, s), 10.89 (1H, s); ESIMSfound for C₁₈H₁₈N₄O m/z 307.1 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexanecarboxamide 120

Beige solid (20.0 mg, 0.056 mmol, 18.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.17-1.34 (3H, m), 1.44 (2H, qd, J=12.21, 2.61 Hz), 1.66(1H, br d, J=11.53 Hz), 1.71-1.79 (2H, m), 1.83 (2H, br d, J=13.17 Hz),2.39 (3H, br s), 2.52-2.62 (1H, m), 3.66 (3H, s), 7.13 (1H, br s), 7.58(1H, dd, J=8.51, 1.37 Hz), 7.89 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.51(1H, s), 9.11 (1H, s), 10.43 (1H, s); ESIMS found for C₂₁H₂₄N₄O m/z349.0 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4,4-difluorocyclohexanecarboxamide121

Off-white solid (40.0 mg, 0.104 mmol, 38.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.66-1.76 (2H, m), 1.77-1.91 (2H, m), 1.92-2.01 (2H, m),2.08-2.21 (2H, m), 2.39 (3H, s), 2.71 (1H, br t, J=10.43 Hz), 3.66 (3H,s), 7.12 (1H, br s), 7.61 (1H, dd, J=8.51, 1.37 Hz), 7.91 (1H, s), 8.08(1H, d, J=8.51 Hz), 8.51 (1H, s), 9.12 (1H, s), 10.63 (1H, s); ESIMSfound for C₂₁H₂₂F₂N₄O m/z 385.2 (M+1).

(S)—N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide188

Light yellow solid (60.0 mg, 0.178 mmol, 57.3% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 1.83-1.95 (2H, m), 1.97-2.07 (1H, m), 2.19-2.30 (1H, m),2.39 (3H, s), 3.67 (3H, s), 3.82-3.91 (1H, m), 3.98-4.07 (1H, m), 4.54(1H, dd, J=8.23, 5.49 Hz), 7.13 (1H, s), 7.64 (1H, dd, J=8.51, 1.65 Hz),7.96 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.50 (1H, s), 9.14 (1H, s), 9.85(1H, s); ESIMS found for C₁₉H₂₀N₄O₂ m/z 337.1 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide248

Off-white solid (99.0 mg, 0.229 mmol, 50.3% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.61-1.74 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.97 (br t,J=11.11 Hz, 2H), 2.40-2.61 (m, 5H), 2.89-3.00 (m, 2H), 4.20 (s, 3H),7.68-7.77 (m, 1H), 8.10 (s, 1H), 8.17-8.21 (m, 2H), 8.60 (s, 1H), 9.21(s, 1H), 10.62 (br s, 1H); ESIMS found for C₂₁H₂₃F₃N₆O m/z 433.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 262

White solid (82.5 mg, 0.191 mmol, 82.4% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.68 (qd, J=12.17, 3.57 Hz, 2H), 1.81 (br d, J=11.25 Hz, 2H),1.97-2.11 (m, 2H), 2.50 (dt, J=3.64, 1.89 Hz, 2H), 2.52-2.62 (m, 3H),2.97 (br d, J=10.43 Hz, 2H), 3.83 (s, 3H), 7.30 (d, J=0.82 Hz, 1H), 7.67(dd, J=8.51, 1.65 Hz, 1H), 7.80 (s, 1H), 8.00 (s, 1H), 8.08 (d, J=8.51Hz, 1H), 8.54 (s, 1H), 9.12 (s, 1H), 10.55 (s, 1H); ESIMS found forC₂₂H₂₄F₃N₅O m/z 432.2 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexanecarboxamide 263

White solid (60.0 mg, 0.162 mmol, 46.0% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.63-1.76 (m, 2H), 1.76-1.91 (m, 2H), 1.95 (br d, J=12.90 Hz,2H), 2.06-2.20 (m, 2H), 2.71 (br t, J=10.84 Hz, 1H), 3.83 (s, 3H), 7.30(d, J=0.82 Hz, 1H), 7.67 (dd, J=8.37, 1.78 Hz, 1H), 7.79 (s, 1H), 8.01(d, J=0.82 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.53 (s, 1H), 9.13 (s, 1H),10.64 (s, 1H); ESIMS found for C₂₀H₂₀F₂N₄O m/z 371.2 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide264

White solid (36.5 mg, 0.104 mmol, 48.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.60-1.72 (m, 2H), 1.74-1.80 (m, 2H), 1.86 (td, J=11.60, 2.06Hz, 2H), 2.16 (s, 3H), 2.45-2.56 (m, 1H), 2.81 (br d, J=11.25 Hz, 2H),3.93 (s, 3H), 6.93 (d, J=2.20 Hz, 1H), 7.81 (d, J=2.20 Hz, 1H),7.95-8.01 (m, 1H), 8.01-8.08 (m, 1H), 8.20 (s, 1H), 8.49 (s, 1H), 9.07(s, 1H), 10.49 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.2 (M+1).

N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide 265

Off-white solid (168.0 mg, 0.504 mmol, 87.3% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 0.78-0.90 (m, 4H), 2.03-2.13 (m, 1H), 2.77 (br s, 1H),3.07 (t, J=5.35 Hz, 2H), 3.95 (s, 2H), 4.10 (t, J=5.35 Hz, 2H), 7.28 (s,1H), 7.65 (dd, J=8.51, 1.65 Hz, 1H), 7.91 (s, 1H), 8.06 (d, J=8.51 Hz,1H), 8.49 (s, 1H), 9.10 (s, 1H), 10.87 (s, 1H); ESIMS found forC₁₉H₁₉N₅O m/z 334.1 (M+1).

N-(6-(7-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide266

White solid (75.0 mg, 0.216 mmol, 69.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.77-0.90 (m, 4H), 2.01-2.13 (m, 1H), 2.42 (s, 3H), 2.80 (t,J=5.35 Hz, 2H), 3.63 (s, 2H), 4.21 (t, J=5.35 Hz, 2H), 7.29 (s, 1H),7.66 (dd, J=8.51, 1.65 Hz, 1H), 7.95 (s, 1H), 8.06 (d, J=8.51 Hz, 1H),8.49 (s, 1H), 9.10 (s, 1H), 10.87 (s, 1H); ESIMS found for C₂₀H₂₁N₅O m/z348.2 (M+1).

3,3-Difluoro-N-(6-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)cyclobutanecarboxamide 267

Beige solid (65.0 mg, 0.164 mmol, 28.5% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 2.55 (br s, 2H), 2.75-2.88 (m, 4H), 2.93-3.10 (m, 1H),3.94-4.10 (m, 1H), 4.21 (br s, 2H), 7.66 (dd, J=8.51, 1.65 Hz, 1H), 7.79(s, 1H), 8.02 (s, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.52 (s, 1H), 9.08 (s,1H), 10.76 (s, 1H); ESIMS found for C₂₁H₂₁F₂N₅O m/z 398.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3,3-difluorocyclobutanecarboxamide268

White solid (67.0 mg, 0.188 mmol, 49.3% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 2.39 (s, 3H), 2.76-2.92 (m, 4H), 3.27-3.36 (m, 1H), 3.67 (s,3H), 7.12 (s, 1H), 7.62 (dd, J=8.51, 1.65 Hz, 1H), 7.93 (s, 1H), 8.09(d, J=8.51 Hz, 1H), 8.55 (s, 1H), 9.13 (s, 1H), 10.80 (s, 1H); ESIMSfound for C₁₉H₁₈F₂N₄O m/z 357.1 (M+1).

2,2,3,3-Tetramethyl-N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]cyclopropanecarboxamide269

Light yellow solid (132.0 mg, 0.379 mmol, 65.3% yield). ¹H NMR (DMSO-d₆,500 MHz) δ ppm 1.19 (s, 6H), 1.28 (s, 6H), 1.63 (s, 1H), 3.83 (s, 3H),7.26-7.40 (m, 1H), 7.64 (dd, J=8.51, 1.37 Hz, 1H), 7.75-7.87 (m, 1H),8.00 (s, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.52 (s, 1H), 9.09 (s, 1H), 10.51(s, 1H); ESIMS found for C₂₁H₂₄N₄O m/z 349.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 270

Off-white solid (45.0 mg, 0.104 mmol, 44.9% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.61-1.75 (m, 2H), 1.75-1.86 (m, 2H), 1.98 (br d, J=1.92 Hz,2H), 2.42-2.63 (m, 5H), 2.95 (br d, J=1.10 Hz, 2H), 3.97 (s, 3H), 6.60(d, J=1.92 Hz, 1H), 7.54 (d, J=1.92 Hz, 1H), 7.66 (dd, J=8.37, 1.51 Hz,1H), 8.07 (s, 1H), 8.14 (d, J=8.51 Hz, 1H), 8.58 (s, 1H), 9.18 (s, 1H),10.60 (s, 1H); ESIMS found for C₂₂H₂₄F₃N₅O m/z 432.2 (M+1).

2-(4-Isobutylpiperazin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide272

Off-white solid (39.0 mg, 0.096 mmol, 29.1% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 0.85 (d, J=6.59 Hz, 6H), 1.76 (dquin, J=13.64, 6.81, 6.81,6.81, 6.81 Hz, 1H), 2.06 (d, J=7.41 Hz, 2H), 2.41 (br s, 4H), 2.58 (brs, 4H), 3.22 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02(d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.04 (s,1H), 9.92 (s, 1H); ESIMS found for C₂₃H₃₀N₆O m/z 407.2 (M+1).

2-(3,3-Dimethylazetidin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide273

Off-white solid (51.0 mg, 0.146 mmol, 44.2% yield). ¹H NMR (DMSO-d₆, 500MHz) δ ppm 1.23 (s, 6H), 3.10 (s, 4H), 3.31 (s, 2H), 3.90 (s, 3H), 7.77(dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.36(s, 1H), 8.41 (s, 1H), 9.04 (s, 1H), 9.88 (s, 1H); ESIMS found forC₂₀H₂₃N₅O m/z 350.2 (M+1).

N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 276

White solid (61.0 mg, 0.174 mmol, 51.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.44 (br d, J=5.21 Hz, 2H), 1.59 (quin, J=5.56 Hz, 4H),2.53 (br s, 4H), 3.18 (s, 2H), 4.14 (s, 3H), 8.04 (dd, J=8.51, 1.65 Hz,1H), 8.13 (d, J=8.51 Hz, 1H), 8.34 (s, 1H), 8.50 (s, 1H), 8.74 (s, 1H),9.13 (s, 1H), 9.97 (s, 1H); ESIMS found for C₁₉H₂₂N₆O m/z 351.2 (M+1).

2,2,3,3-Tetramethyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide 277

White solid (6.0 mg, 0.017 mmol, 6.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.19 (s, 6H), 1.29 (s, 6H), 1.63 (s, 1H), 4.14 (s, 3H), 7.99 (dd,J=8.51, 1.37 Hz, 1H), 8.09 (d, J=8.51 Hz, 1H), 8.28 (s, 1H), 8.47 (s,1H), 8.69 (s, 1H), 9.09 (s, 1H), 10.50 (s, 1H); ESIMS found forC₂₀H₂₃N₅O m/z 350.2 (M+1).

N-(6-(4-Methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide278

Off-white solid (30.0 mg, 0.069 mmol, 30.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.74 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.92-2.03(m, 2H), 2.40-2.49 (m, 2H), 2.51-2.62 (m, 3H), 2.94 (br d, J=11.25 Hz,2H), 3.88 (s, 3H), 7.90 (dd, J=8.51, 1.65 Hz, 1H), 8.19 (d, J=8.51 Hz,1H), 8.27 (s, 1H), 8.63 (s, 1H), 8.65 (s, 1H), 9.22 (s, 1H), 10.63 (s,1H); ESIMS found for C₂₁H₂₃F₃N₆O m/z 433.2 (M+1).

N-(6-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide279

Light pink solid (53.0 mg, 0.119 mmol, 51.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.73 (m, 2H), 1.80 (br d, J=11.53 Hz, 2H), 1.92-2.04(m, 2H), 2.40-2.49 (m, 5H), 2.51-2.61 (m, 3H), 2.94 (br d, J=10.98 Hz,2H), 3.70 (s, 3H), 7.82 (dd, J=8.51, 1.65 Hz, 1H), 8.14-8.22 (m, 2H),8.62 (s, 1H), 9.21 (s, 1H), 10.63 (s, 1H); ESIMS found for C₂₂H₂₅F₃N₆Om/z 447.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(4-methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 280

White solid (38.0 mg, 0.093 mmol, 25.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.79 (dquin, J=13.46, 6.79,6.79, 6.79, 6.79 Hz, 1H), 1.92-2.02 (m, 2H), 2.09 (d, J=7.41 Hz, 3H),2.12-2.21 (m, 3H), 2.74-2.83 (m, 2H), 3.89 (s, 3H), 7.97 (dd, J=8.51,1.65 Hz, 1H), 8.24 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.60 (s, 1H), 8.66(s, 1H), 9.28 (s, 1H), 10.06 (d, J=3.84 Hz, 1H); ESIMS found forC₂₂H₂₇FN₆O m/z 411.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 281

Off-white solid (31.0 mg, 0.076 mmol, 20.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.79 (dquin, J=13.52, 6.71,6.71, 6.71, 6.71 Hz, 1H), 1.91-2.01 (m, 2H), 2.06-2.22 (m, 6H), 2.78 (brd, J=7.96 Hz, 2H), 4.15 (s, 3H), 8.07 (dd, J=8.51, 1.65 Hz, 1H), 8.16(d, J=8.78 Hz, 1H), 8.37 (s, 1H), 8.47 (s, 1H), 8.74 (s, 1H), 9.17 (s,1H), 9.95 (d, J=4.12 Hz, 1H); ESIMS found for C₂₂H₂₇FN₆O m/z 411.2(M+1).

1-Ethyl-4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 282

Beige solid (6.0 mg, 0.016 mmol, 5.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.03 (t, J=7.14 Hz, 3H), 1.93-2.02 (m, 2H), 2.05-2.13 (m, 1H),2.13-2.20 (m, 3H), 2.39 (q, J=7.14 Hz, 2H), 2.80-2.88 (m, 2H), 4.15 (s,3H), 8.03-8.10 (m, 1H), 8.16 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.47 (s,1H), 8.73 (s, 1H), 9.17 (s, 1H), 9.94 (d, J=4.12 Hz, 1H); ESIMS foundfor C₂₀H₂₃FN₆O m/z 383.2 (M+1).

4,4-Difluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide283

Beige solid (7.7 mg, 0.017 mmol, 12.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.66-1.77 (m, 2H), 1.77-1.91 (m, 2H), 1.92-2.01 (m, 2H), 2.08-2.19(m, 2H), 2.67-2.76 (m, 1H), 2.96 (t, J=4.80 Hz, 1H), 3.01 (t, J=4.80 Hz,1H), 3.07 (t, J=5.35 Hz, 2H), 4.08 (s, 2H), 4.18 (t, J=5.35 Hz, 2H),4.66 (dt, J=47.85, 4.95 Hz, 2H), 7.64 (dd, J=8.51, 1.37 Hz, 1H), 7.76(s, 1H), 8.00 (s, 1H), 8.03 (d, J=8.78 Hz, 1H), 8.47 (s, 1H), 9.06 (s,1H), 10.58 (s, 1H); ESIMS found for C₂₄H₂₆F₃N₅O m/z 458.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 284

White gummy paste (53.0 mg, 0.150 mmol, 45.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (dt, J=6.52, 3.19 Hz, 4H), 2.66 (br t, J=5.90 Hz,4H), 3.35 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02(d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.03 (s,1H), 9.92 (s, 1H); ESIMS found for C₁₉H₂₁N₅O m/z 336.2 (M+1).

N-(6-(1-Ethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 285

Dark pink paste (42.0 mg, 0.114 mmol, 63.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.44 (t, J=7.27 Hz, 3H), 1.78 (dt, J=6.66, 3.12 Hz, 4H),2.62-2.69 (m, 4H), 3.35 (s, 2H), 4.18 (q, J=7.41 Hz, 2H), 7.78 (dd,J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.09-8.14 (m, 2H), 8.43(s, 2H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 286

White paste (68.0 mg, 0.179 mmol, 59.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.98-1.05 (m, 2H), 1.08-1.13 (m, 2H), 1.78 (dt, J=6.86,3.16 Hz, 4H), 2.62-2.69 (m, 4H), 3.35 (s, 2H), 3.78 (tt, J=7.34, 3.77Hz, 1H), 7.79 (dd, J=8.51, 1.65 Hz, 1H), 8.01 (d, J=8.78 Hz, 1H),8.08-8.15 (m, 2H), 8.43 (s, 1H), 8.48 (s, 1H), 9.03 (s, 1H), 9.92 (s,1H); ESIMS found for C₂₁H₂₃N₅O m/z 362.2 (M+1).

2-(Pyrrolidin-1-yl)-N-(6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide287

White solid (83.0 mg, 0.203 mmol, 45.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (dt, J=6.72, 3.22 Hz, 4H), 2.61-2.70 (m, 4H), 3.36(s, 2H), 7.60 (dd, J=8.37, 1.24 Hz, 1H), 7.93 (s, 1H), 8.12 (d, J=8.51Hz, 1H), 8.40 (s, 1H), 8.46 (s, 1H), 9.14 (s, 1H), 10.01 (s, 1H); ESIMSfound for C₁₉H₈F₃N₅O m/z 390.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide 288

White solid (58.8 mg, 0.158 mmol, 50.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30 (d, J=6.86 Hz, 3H), 1.74 (br s, 4H), 2.57-2.69 (m,4H), 3.28 (q, J=6.95 Hz, 1H), 3.90 (s, 3H), 7.76 (dd, J=8.51, 1.65 Hz,1H), 8.02 (d, J=8.51 Hz, 1H), 8.06-8.12 (m, 2H), 8.36 (s, 1H), 8.43 (s,1H), 9.03 (s, 1H), 9.95 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.1(M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide289

White paste (79.5 mg, 0.216 mmol, 65.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.04 Hz, 3H), 1.42 (dddd, J=12.25, 10.33,8.30, 6.45 Hz, 1H), 1.66-1.83 (m, 2H), 1.91-2.02 (m, 1H), 2.40 (q,J=8.78 Hz, 1H), 2.56-2.66 (m, 1H), 3.12 (d, J=16.19 Hz, 1H), 3.14-3.19(m, 1H), 3.54 (d, J=16.47 Hz, 1H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65Hz, 1 H), 8.02 (d, J=8.51 Hz, 1H), 8.07-8.14 (m, 2H), 8.37 (s, 1H), 8.44(s, 1H), 9.03 (s, 1H), 9.89 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide290

White solid (77.0 mg, 0.209 mmol, 66.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.04 Hz, 3H), 1.42 (dddd, J=12.32, 10.39,8.30, 6.31 Hz, 1H), 1.66-1.84 (m, 2H), 1.91-2.01 (m, 1H), 2.40 (q,J=8.78 Hz, 1H), 2.57-2.66 (m, 1H), 3.12 (d, J=16.47 Hz, 1H), 3.14-3.19(m, 1H), 3.54 (d, J=16.19 Hz, 1H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.08-8.13 (m, 2H), 8.37 (s, 1H), 8.44(s, 1H), 9.03 (s, 1H), 9.88 (s, 1H); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 291

White solid (72.0 mg, 0.207 mmol, 62.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.44 (td, J=7.55, 4.12 Hz, 1H), 0.70 (q, J=3.84 Hz, 1H),1.40-1.48 (m, 2H), 2.57 (br d, J=8.23 Hz, 2H), 3.04 (d, J=8.78 Hz, 2H),3.33 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d,J=8.51 Hz, 1H), 8.09 (s, 2H), 8.36 (s, 1H), 8.41 (s, 1H), 9.03 (s, 1H),9.77 (s, 1H); ESIMS found for C₂₀H₂₁N₅O m/z 348.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 292

Beige solid (64.0 mg, 0.177 mmol, 53.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34 (br d, J=6.86 Hz, 4H), 1.74 (br d, J=6.59 Hz, 4H),3.19 (s, 2H), 3.34-3.39 (m, 2 H), 3.90 (s, 3H), 7.74-7.83 (m, 1H), 8.02(d, J=8.78 Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.46 (s, 1H), 9.04(s, 1H), 10.08 (s, 1H); ESIMS found for C₂₁H₂₃N₅O m/z 362.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide293

White solid (56.0 mg, 0.146 mmol, 44.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.93 (d, J=6.59 Hz, 3H), 1.18-1.29 (m, 2H), 1.32-1.43 (m,1H), 1.64 (br d, J=11.25 Hz, 2H), 2.20 (td, J=11.53, 1.92 Hz, 2H), 2.87(br d, J=11.53 Hz, 2H), 3.18 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51,1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43(s, 1H), 9.04 (s, 1H), 9.90 (s, 1H); ESIMS found for C₂₁H₂₅N₅O m/z 364.2(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide 294

Off-white solid (92.0 mg, 0.209 mmol, 63.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.56 (qd, J=12.44, 3.84 Hz, 2H), 1.83 (br d, J=12.62 Hz,2H), 2.28 (td, J=11.94, 1.92 Hz, 2H), 2.30-2.39 (m, 1H), 3.00 (br d,J=11.53 Hz, 2H), 3.25 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.64, 1.51 Hz,1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.44 (s, 1H),9.04 (s, 1H), 9.98 (s, 1H); ESIMS found for C₂₁H₂₂F₃N₅O m/z 418.2 (M+1).

2-(4-(Difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 295

Beige solid (70.0 mg, 0.167 mmol, 62.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.47 (qd, J=12.44, 3.84 Hz, 2H), 1.71 (br d, J=12.35 Hz,2H), 1.75-1.90 (m, 1H), 2.23 (td, J=11.80, 1.92 Hz, 2H), 2.97 (br d,J=11.53 Hz, 2H), 3.23 (s, 2H), 3.90 (s, 3H), 5.95 (td, J=56.90, 4.40 Hz,1H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s,2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 9.93 (s, 1H); ESIMS foundfor C₂₁H₂₃F₂N₅O m/z 400.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide296

Off-white solid (60.0 mg, 0.152 mmol, 56.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.29 (s, 4H), 1.42 (br s, 4H), 2.56-2.64 (m, 4H), 3.24(s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.51Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H),9.96 (s, 1H); ESIMS found for C₂₂H₂₅N₅O m/z 376.2 (M+1).

N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide297

Off-white solid (21.0 mg, 0.046 mmol, 24.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.97-1.06 (m, 2H), 1.08-1.14 (m, 2H), 1.60-1.73 (m, 2H),1.79 (br d, J=10.43 Hz, 2H), 1.92-2.02 (m, 2H), 2.40-2.60 (m, 5H), 2.93(br d, J=11.25 Hz, 2H), 3.78 (tt, J=7.44, 3.81 Hz, 1H), 7.76 (dd,J=8.51, 1.37 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.04-8.11 (m, 2H), 8.45(d, J=9.06 Hz, 2H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found forC₂₄H₂₆F₃N₅O m/z 458.2 (M+1).

N-(6-(5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-1-carboxamide298

Beige solid (4.4 mg, 0.010 mmol, 3.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.67-2.02 (m, 8H), 2.07-2.19 (m, 2H), 2.67-2.77 (m, 1H), 3.11 (t,J=6.86 Hz, 4H), 3.77 (s, 2H), 3.92 (s, 3H), 7.67 (dd, J=8.51, 1.37 Hz,1H), 7.75 (s, 1H), 7.93 (s, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.46 (s, 1H),9.09 (s, 1H), 10.60 (s, 1H); ESIMS found for C₂₄H₂₇F₂N₅O m/z 440.2(M+1).

4,4-Difluoro-N-(6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 299

Beige solid (26.4 mg, 0.058 mmol, 23.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67 (br s, 4H), 1.69-1.91 (m, 4H), 1.95 (br d, J=12.90Hz, 2H), 2.06-2.18 (m, 2H), 2.44 (br s, 4H), 2.71 (br t, J=10.84 Hz,1H), 3.83 (s, 2H), 3.92 (s, 3H), 7.68 (dd, J=8.51, 1.65 Hz, 1H), 7.78(s, 1H), 7.96 (s, 1H), 8.03 (d, J=8.51 Hz, 1H), 8.44 (s, 1H), 9.08 (s,1H), 10.59 (s, 1H); ESIMS found for C₂₅H₂₉F₂N₅O m/z 454.2 (M+1).

4,4-Difluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 300

White solid (10.6 mg, 0.023 mmol, 18.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.38 (br d, J=4.12 Hz, 2H), 1.44-1.53 (m, 4H), 1.66-1.90(m, 4H), 1.92-2.01 (m, 2H), 2.06-2.18 (m, 2H), 2.36 (br d, J=1.65 Hz,4H), 2.65-2.76 (m, 1H), 3.65 (s, 2H), 3.91 (s, 3H), 7.70 (dd, J=8.51,1.65 Hz, 1H), 7.80 (s, 1H), 7.98-8.07 (m, 2H), 8.45 (s, 1H), 9.08 (s,1H), 10.58 (s, 1H); ESIMS found for C₂₆H₃₁F₂N₅O m/z 468.2 (M+1).

7-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide301

Beige solid (50.0 mg, 0.119 mmol, 18.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53 (br t, J=5.35 Hz, 2H), 1.59 (br t, J=5.35 Hz, 2H),1.97 (d, J=8.51 Hz, 4H), 2.30 (br s, 2H), 2.33-2.44 (m, 2H), 2.55 (dt,J=28.30, 5.20 Hz, 2H), 3.33-3.42 (m, 1H), 3.90 (s, 3H), 4.50 (dt,J=48.10, 5.25 Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.46 (s, 1H), 9.01(s, 1H), 10.34 (s, 1H); ESIMS found for C₂₄H₂₈FN₅O m/z 422.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide302

Off-white solid (69.0 mg, 0.198 mmol, 59.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53-1.69 (m, 2H), 1.81-1.92 (m, 2H), 1.97-2.07 (m, 2H),2.23 (s, 3H), 3.03-3.10 (m, 1H), 3.11 (s, 2H), 3.90 (s, 3H), 7.77 (dd,J=8.51, 1.37 Hz, 1H), 8.03 (d, J=8.51 Hz, 1H), 8.08-8.14 (m, 2H), 8.37(s, 1H), 8.43 (s, 1H), 9.04 (s, 1H), 9.91 (s, 1H); ESIMS found forC₂₀H₂₃N₅O m/z 350.2 (M+1).

2-(Diethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 303

White paste (74.0 mg, 0.219 mmol, 66.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.05 (t, J=7.14 Hz, 6H), 2.65 (q, J=7.14 Hz, 4H), 3.24(s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H),9.93 (s, 1H); ESIMS found for C₁₉H₂₃N₅O m/z 338.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide304

Off-white solid (54.0 mg, 0.124 mmol, 44.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.72 (m, 2H), 1.79 (br d, J=10.15 Hz, 2H), 1.91-2.02(m, 2H), 2.39-2.60 (m, 5H), 2.93 (br d, J=11.25 Hz, 2H), 7.74 (dd,J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s,1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMSfound for C₂₂H₂₁D₃F₃N₅O m/z 435.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 305

White paste (80.0 mg, 0.236 mmol, 71.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (dt, J=6.59, 3.29 Hz, 4H), 2.62-2.70 (m, 4H), 3.35(s, 2H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10(s, 2H), 8.36 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMSfound for C₁₉H₁₈D₃N₅O m/z 339.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 306

Beige solid (82.0 mg, 0.233 mmol, 70.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (br d, J=4.94 Hz, 2H), 1.59 (quin, J=5.56 Hz, 4H),2.52 (br d, J=1.92 Hz, 4H), 3.17 (s, 2H), 7.77 (dd, J=8.51, 1.65 Hz,1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (s, 2H), 8.36 (s, 1H), 8.43 (s, 1H),9.04 (s, 1H), 9.91 (s, 1H); ESIMS found for C₂₀H₂₀D₃N₅O m/z 353.2 (M+1).

N-(6-(3-Methylisoxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 307

White solid (3.0 mg, 0.007 mmol, 2.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.61-1.73 (m, 2H), 1.80 (br d, J=10.43 Hz, 2H), 1.92-2.02 (m, 2H),2.41-2.61 (m, 5H), 2.51 (s, 3H), 2.93 (br d, J=11.25 Hz, 2H), 7.68 (dd,J=8.37, 1.51 Hz, 1H), 8.04 (s, 1H), 8.11 (d, J=8.51 Hz, 1H), 8.54 (s,1H), 9.13 (s, 1H), 9.34 (s, 1H), 10.56 (s, 1H); ESIMS found forC₂₂H₂₃F₃N₄O₂ m/z 433.2 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide308

Off-white solid (16.0 mg, 0.038 mmol, 16.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.58-1.72 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.91-2.03(m, 2H), 2.40-2.61 (m, 5H), 2.94 (br d, J=11.25 Hz, 2H), 7.87 (dd,J=8.64, 1.51 Hz, 1H), 7.95 (s, 1H), 8.13 (d, J=8.51 Hz, 1H), 8.20 (s,1H), 8.54 (s, 1H), 8.58 (s, 1H), 9.13 (s, 1H), 10.58 (s, 1H); ESIMSfound for C₂₁H₂₁F₃N₄O₂ m/z 419.1 (M+1).

4-Fluoro-1-isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 309

Off-white solid (20.0 mg, 0.049 mmol, 13.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.80 (dquin, J=13.55, 6.84,6.84, 6.84, 6.84 Hz, 1H), 1.92-2.02 (m, 2H), 2.09 (d, J=7.41 Hz, 2H),2.06-2.21 (m, 4H), 2.64 (s, 3H), 2.75-2.82 (m, 2H), 8.11 (dd, J=8.51,1.65 Hz, 1H), 8.29 (d, J=8.51 Hz, 1H), 8.57 (s, 1H), 8.60 (s, 1H), 9.30(s, 1H), 10.11 (d, J=3.57 Hz, 1H); ESIMS found for C₂₂H₂₆FN₅O₂ m/z 412.2(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 310

Off-white solid (70.0 mg, 0.153 mmol, 76.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.73 (s, 2H), 0.93-0.99 (m, 2H), 1.60-1.72 (m, 2H),1.73-1.82 (m, 2H), 1.89-2.00 (m, 2H), 2.49 (br s, 2H), 2.52-2.58 (m,1H), 2.96 (br d, J=11.25 Hz, 2H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s,1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found forC₂₄H₂₆F₃N₅O m/z 458.2 (M+1).

(S)-1-(2-Fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 311

White solid (71.0 mg, 0.180 mmol, 60.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.26 (dd, J=23.95, 6.35 Hz, 3H), 1.62-1.72 (m, 2H),1.74-1.82 (m, 2H), 2.00-2.12 (m, 2H), 2.34-2.49 (m, 2H), 2.52-2.59 (m,1H), 2.93 (brt, J=11.80 Hz, 2H), 3.90 (s, 3H), 4.75-4.94 (m, 1H), 7.74(dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.04 (s, 1H), 8.07(s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMSfound for C₂₂H₂₆FN₅O m/z 396.2 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)propanamide 312

Off-white solid (21.0 mg, 0.067 mmol, 10.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64 (d, J=22.00 Hz, 6H), 4.15 (s, 3H), 8.07 (dd, J=8.51,1.65 Hz, 1H), 8.16 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.46 (s, 1H), 8.74(s, 1H), 9.17 (s, 1H), 9.91 (d, J=3.57 Hz, 1H); ESIMS found forC₁₆H₁₆FN₅O m/z 314.1 (M+1).

(R)-1-(2-Fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 313

White solid (30.0 mg, 0.076 mmol, 25.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.26 (dd, J=23.90, 6.30 Hz, 3H), 1.68 (q, J=11.53 Hz,2H), 1.74-1.81 (m, 2H), 1.99-2.09 (m, 2H), 2.35-2.47 (m, 1H), 2.52-2.57(m, 1H), 2.93 (br t, J=11.80 Hz, 2H), 3.90 (s, 3H), 4.74-4.94 (m, 1H),7.74 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H),8.07 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H);ESIMS found for C₂₂H₂₆FN₅O m/z 396.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide 314

Off-white solid (57.0 mg, 0.157 mmol, 51.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.20 (d, J=7.14 Hz, 3H), 1.39-1.46 (m, 2H), 1.53-1.64 (m,4H), 2.52-2.58 (m, 2H), 3.44 (q, J=6.86 Hz, 1H), 3.90 (s, 3H), 7.76 (dd,J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.06-8.11 (m, 2H), 8.36(s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 10.09 (s, 1H); ESIMS found forC₂₁H₂₅N₅O m/z 364.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d₄)acetamide315

Beige solid (43.0 mg, 0.127 mmol, 42.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76 (s, 4H), 3.36 (s, 2H), 3.90 (s, 3H), 7.77 (dd,J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s,1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.93 (s, 1H); ESIMS found forC₁₉H₁₇D₄N₅O m/z 340.2 (M+1).

4-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide316

Off-white solid (14.0 mg, 0.040 mmol, 46.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.20 (s, 3H), 2.29-2.35 (m, 4H), 3.48-3.54 (m, 4H), 3.90(s, 3H), 7.68 (dd, J=8.51, 1.65 Hz, 1H), 7.94-8.00 (m, 2H), 8.06 (s,1H), 8.14 (s, 1H), 8.33 (s, 1H), 8.97 (s, 1H), 9.13 (s, 1H); ESIMS foundfor C₁₉H₂₂N₆O m/z 351.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide 317

White solid (75.0 mg, 0.215 mmol, 65.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.57-2.68 (4H,m), 3.25-3.30 (1H, m), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz),8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.43(1H, s), 9.03 (1H, s), 9.94 (1H, s); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide 318

Light beige solid (89.0 mg, 0.255 mmol, 62.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.70 (4H,m), 3.25-3.30 (1H, m), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz),8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.43(1H, s), 9.03 (1H, s), 9.94 (1H, s); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide320

Brown solid (830.0 mg, 2.58 mmol, 78.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67 (2H, quin, J=6.86 Hz), 1.79-1.90 (1H, m), 2.04-2.16(1H, m), 2.87 (1H, dt, J=10.15, 6.31 Hz), 2.97 (1H, dt, J=10.15, 6.72Hz), 3.35 (1H, br s), 3.80 (1H, dd, J=9.19, 5.35 Hz), 3.90 (3H, s), 7.76(1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.09 (1H, br s),8.09 (1H, s), 8.36 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.34 (1H, s);ESIMS found for C₁₈H₁₉N₅O m/z 322.15 (M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide324

Off-white solid (32.0 mg, 0.089 mmol, 38.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.15 (3H, s), 2.21-2.35 (4H, m), 3.04 (2H, s), 3.14 (2H,s), 3.21-3.28 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz),7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44(1H, s), 9.01 (1H, s), 10.35 (1H, s); ESIMS found for C₂₁H₂₃N₅O m/z362.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide325

White solid (26.0 mg, 0.059 mmol, 18.0% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.40-2.49 (4H, m), 3.22-3.31 (1H, m), 4.06-4.15 (2H, m),4.44 (2H, br d, J=17.56 Hz), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H,d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, d, J=1.10 Hz), 8.35 (1H, d,J=1.65 Hz), 8.46 (1H, s), 9.02 (1H, s), 10.47 (1H, s); ESIMS found forC₂₂H₂₀F₃N₅O₂ m/z 444.15 (M+1).

2-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide326

Beige solid (10.0 mg, 0.025 mmol, 24.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23-2.36 (4H, m), 2.60 (2H, dt, J=29.00, 5.00 Hz), 3.13(2H, s), 3.22 (2H, s), 3.24-3.29 (1H, m), 4.36 (2H, dt, J=48.00, 5.00Hz), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H,s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.01 (1H, s), 10.36 (1H,s); ESIMS found for C₂₂H₂₄FN₅O m/z 394.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide327

Beige solid (650.0 mg, 1.72 mmol, 46.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.11-1.27 (3H, m), 1.41-1.54 (2H, m), 1.83-1.96 (4H, m),2.10-2.16 (1H, m), 2.18 (6H, s), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74(1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07(1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMSfound for C₂₂H₂₇N₅O m/z 378.2 (M+1).

1-Benzoyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide328

White solid (65.0 mg, 0.148 mmol, 55.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.57-1.72 (2H, m), 1.75-2.00 (2H, m), 2.86 (2H, tt,J=11.18, 3.77 Hz), 3.04-3.19 (1H, m), 3.57-3.75 (1H, m), 3.90 (3H, s),4.43-4.63 (1H, m), 7.38-7.43 (2H, m), 7.43-7.49 (3H, m), 7.75 (1H, dd,J=8.51, 1.37 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s),8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 10.54 (1H, s); ESIMS found forC₂₆H₂₅N₅O₂ m/z 440.0 (M+1).

1-Acetyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide329

White solid (60.0 mg, 0.159 mmol, 59.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.47 (1H, qd, J=12.26, 4.39 Hz), 1.56-1.69 (1H, m),1.77-1.91 (2H, m), 2.02 (3H, s), 2.58 (1H, td, J=12.62, 2.47 Hz),2.75-2.84 (1H, m), 3.03-3.11 (1H, m), 3.88 (1H, br d, J=13.15 Hz), 3.90(3H, s), 4.41 (1H, br d, J=13.17 Hz), 7.75 (1H, dd, J=8.51, 1.65 Hz),8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.43(1H, s), 9.03 (1H, s), 10.53 (1H, s); ESIMS found for C₂₁H₂₃N₅O₂ m/z378.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide 330

White solid (60.0 mg, 0.145 mmol, 54.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.65-1.77 (2H, m), 1.95 (2H, br dd, J=13.31, 2.61 Hz),2.69 (1H, tt, J=11.25, 3.84 Hz), 2.76 (2H, td, J=11.94, 2.20 Hz), 2.89(3H, s), 3.59-3.67 (2H, m), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65Hz), 8.01 (1H, d, J=8.51 Hz), 8.05 (1H, s), 8.08 (1H, s), 8.35 (1H, s),8.44 (1H, s), 9.03 (1H, s), 10.59 (1H, s); ESIMS found for C₂₀H₂₃N₅O₃Sm/z 413.9 (M+1).

1′-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide331

White solid (4.0 mg, 0.009 mmol, 3.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.44 (2H, qd, J=11.89, 3.57 Hz), 1.58-1.71 (4H, m), 1.73-1.87 (4H,m), 2.06-2.20 (4H, m), 2.12 (3H, s), 2.78 (2H, br d, J=11.53 Hz), 2.91(2H, br d, J=11.25 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37 Hz),7.99 (1H, d, J=8.78 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44(1H, s), 9.02 (1H, s), 10.42 (1H, s); ESIMS found for C₂₅H₃₂N₆O m/z433.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide332

White solid (11.0 mg, 0.026 mmol, 8.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.43 (2H, qd, J=12.08, 4.39 Hz), 1.59-1.69 (4H, m), 1.79 (2H, brd, J=11.80 Hz), 2.08-2.17 (2H, m), 2.42 (1H, tt, J=11.35, 3.60 Hz),2.51-2.58 (1H, m), 2.94 (2H, br d, J=11.53 Hz), 3.22-3.29 (2H, m), 3.87(2H, br d, J=3.57 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz),7.99 (1H, d, J=8.78 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44(1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found for C₂₄H₂₉N₅O₂ m/z420.0 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide333

Light beige solid (215.0 mg, 0.59 mmol, 51.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.95 (2H, qd, J=12.72, 3.29 Hz), 1.31-1.39 (1H, m), 1.45(2H, qd, J=12.72, 3.02 Hz), 1.80 (2H, br dd, J=13.17, 2.74 Hz),1.84-1.93 (2H, m), 3.24 (2H, t, J=5.76 Hz), 3.90 (3H, s), 4.37 (1H, t,J=5.35 Hz), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz),8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.02 (1H, s),10.38 (1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.0 (M+1).

Methyl 2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate 334

White solid (20.0 mg, 0.049 mmol, 16.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.73 (2H, m), 1.74-1.82 (2H, m), 2.22 (2H, td,J=11.53, 2.20 Hz), 2.51-2.58 (1H, m), 2.84-2.92 (2H, m), 3.24 (2H, s),3.62 (3H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d,J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02(1H, s), 10.45 (1H, s); ESIMS found for C₂₂H₂₅N₅O₃ m/z 408.0 (M+1).

1-Benzyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide335

White solid (22.0 mg, 0.052 mmol, 17.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.72 (2H, m), 1.73-1.81 (2H, m), 1.98 (2H, td,J=11.60, 2.06 Hz), 2.51-2.57 (1H, m), 2.88-2.96 (2H, m), 3.24 (2H, s),3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.78 Hz),8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s),10.43 (1H, s); ESIMS found for C₂₆H₂₇N₅O m/z 426.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide 336

White solid (21.0 mg, 0.047 mmol, 15.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.43-1.54 (1H, m), 1.55-1.66 (1H, m), 1.67-1.73 (4H, m),1.84 (2H, br d, J=10.98 Hz), 2.48 (4H, br s), 2.56-2.66 (1H, m),2.76-2.87 (1H, m), 2.97-3.07 (1H, m), 3.32 (2H, br s), 3.90 (3H, s),4.11 (1H, br d, J=13.17 Hz), 4.40 (1H, br d, J=12.90 Hz), 7.75 (1H, dd,J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s),8.34 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 10.52 (1H, s); ESIMS found forC₂₅H₃₀N₆O₂ m/z 447.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide338

Beige solid (13.0 mg, 0.037 mmol, 33.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.60 (3H, m), 3.24 (2H, s), 3.62-3.70 (4H, m), 3.90(3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.09(2H, s), 8.35 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMSfound for C₁₉H₂₁N₅O₂ m/z 352.0 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-2-carboxamide340

Light beige solid (35.0 mg, 0.104 mmol, 56.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31-1.41 (1H, m), 1.41-1.47 (2H, m), 1.47-1.56 (1H, m),1.72-1.79 (1H, m), 1.84-1.91 (1H, m), 2.58-2.64 (1H, m), 2.93-3.00 (1H,m), 3.34 (1H, br dd, J=9.19, 3.16 Hz), 3.90 (3H, s), 7.76 (1H, dd,J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.07 (1H, br s), 8.08 (1H,s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.85 (1H, br s); ESIMSfound for C₁₉H₂₁N₅O m/z 336.0 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide341

Beige solid (32.5 mg, 0.089 mmol, 34.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.95 (3H, d, J=6.59 Hz), 2.52-2.58 (1H, m), 2.58-2.65(1H, m), 2.81 (1H, dt, J=11.80, 2.47 Hz), 3.15-3.23 (2H, m), 3.47 (1H,d, J=16.47 Hz), 3.58 (1H, td, J=10.70, 2.20 Hz), 3.68 (1H, dd, J=11.25,2.74 Hz), 3.71-3.79 (1H, m), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H,s), 8.44 (1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMS found for C₂₀H₂₃N₅O₂m/z 366.2 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide342

Beige solid (37.0 mg, 0.101 mmol, 38.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.96 (3H, d, J=6.59 Hz), 2.55 (1H, ddd, J=11.80, 10.15,3.02 Hz), 2.61 (1H, ddd, J=9.13, 6.24, 3.02 Hz), 2.81 (1H, dt, J=11.73,2.50 Hz), 3.13-3.23 (2H, m), 3.47 (1H, d, J=16.47 Hz), 3.58 (1H, td,J=10.70, 2.20 Hz), 3.68 (1H, dd, J=11.25, 3.02 Hz), 3.74 (1H, dt,J=11.32, 2.71 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02(1H, d, J=8.51 Hz), 8.10 (1H, s), 8.10 (1H, br s), 8.36 (1H, s), 8.43(1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMS found for C₂₀H₂₃N₅O₂ m/z366.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide343

Beige solid (19.0 mg, 0.052 mmol, 15.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.07 (3H, d, J=6.31 Hz), 2.00 (1H, dd, J=10.98, 10.15Hz), 2.30 (1H, td, J=11.39, 3.02 Hz), 2.73-2.79 (1H, m), 2.83 (1H, br d,J=11.25 Hz), 3.23 (2H, d, J=1.92 Hz), 3.53-3.66 (2H, m), 3.75-3.81 (1H,m), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d, J=8.78Hz), 8.10 (2H, s), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 10.00 (1H,s); ESIMS found for C₂₀H₂₃N₅O₂ m/z 366.2 (M+1).

2-((2R,6S)-2,6-Dimethylmorpholino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 344

Off-white solid (53.0 mg, 0.140 mmol, 46.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.07 (6H, d, J=6.31 Hz), 1.92 (2H, t, J=10.84 Hz), 2.82(2H, br d, J=10.15 Hz), 3.22 (2H, s), 3.62-3.71 (2H, m), 3.90 (3H, s),7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s),8.36 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.98 (1H, s); ESIMS found forC₂₁H₂₅N₅O₂ m/z 380.2 (M+1).

2-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide345

Ash colored solid (22.0 mg, 0.061 mmol, 18.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67 (1H, dt, J=9.61, 1.10 Hz), 1.87 (1H, dd, J=9.74,1.78 Hz), 2.62 (1H, d, J=10.43 Hz), 2.95 (1H, dd, J=10.02, 1.51 Hz),3.45 (2H, d, J=5.21 Hz), 3.59 (1H, dd, J=7.82, 1.78 Hz), 3.63 (1H, s),3.88 (1H, d, J=7.68 Hz), 3.90 (3H, s), 4.41 (1H, s), 7.77 (1H, dd,J=8.64, 1.51 Hz), 8.03 (1H, d, J=8.78 Hz), 8.10 (1H, s), 8.11 (1H, brs), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS foundfor C₂₀H₂₁N₅O₂ m/z 364.2 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide346

Ash colored solid (25.0 mg, 0.069 mmol, 18.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.70 (1H, m), 1.87 (1H, dd, J=9.74, 1.78 Hz), 2.62(1H, d, J=10.15 Hz), 2.95 (1H, dd, J=10.02, 1.51 Hz), 3.45 (2H, d,J=4.94 Hz), 3.59 (1H, dd, J=7.68, 1.92 Hz), 3.63 (1H, s), 3.88 (1H, d,J=7.68 Hz), 3.90 (3H, s), 4.41 (1H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz),8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s),8.44 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C₂₀H₂₁N₅O₂ m/z364.2 (M+1).

2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 347

Off-white solid (8.0 mg, 0.021 mmol, 8.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.75-1.82 (2H, m), 1.86-1.94 (2H, m), 3.14 (2H, s), 3.17(2H, br d, J=0.82 Hz), 3.48-3.55 (2H, m), 3.68 (2H, d, J=10.43 Hz), 3.90(3H, s), 7.78 (1H, dd, J=8.51, 1.37 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10(1H, s), 8.11 (1H, s), 8.37 (1H, s), 8.46 (1H, s), 9.06 (1H, s), 10.15(1H, s); ESIMS found for C₂₁H₂₃N₅O₂ m/z 378.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide348

Light yellow solid (68.0 mg, 0.186 mmol, 45.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.23 (3H, d, J=6.86 Hz), 2.51-2.57 (2H, m), 2.57-2.65(2H, m), 3.45 (1H, q, J=6.77 Hz), 3.64 (4H, t, J=4.67 Hz), 3.90 (3H, s),7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s),8.09 (1H, s), 8.36 (1H, s), 8.45 (1H, s), 9.04 (1H, s), 10.17 (1H, s);ESIMS found for C₂₀H₂₃N₅O₂ m/z 366.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide 349

Off-white solid (275.0 mg, 0.783 mmol, 91.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.41-2.48 (2H, m), 2.57-2.69 (3H, m), 2.83 (1H, br dd,J=12.21, 2.06 Hz), 3.43 (1H, td, J=10.63, 3.43 Hz), 3.70 (1H, br d,J=10.70 Hz), 3.78-3.85 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.64, 1.51Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.34 (1H, s),8.43 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C₁₉H₂₁N₅O₂m/z 352.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide350

White solid (71.0 mg, 0.194 mmol, 68.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (1H, t, J=11.00 Hz), 1.97 (1H, td, J=11.32, 3.16Hz), 2.18 (3H, s), 2.53 (1H, br d, J=5.49 Hz), 2.58 (1H, br dd, J=11.25,1.37 Hz), 2.66 (1H, dd, J=14.68, 7.82 Hz), 2.74 (1H, br d, J=11.25 Hz),3.50 (1H, td, J=11.11, 2.47 Hz), 3.72-3.80 (1H, m), 3.86-3.96 (1H, m),3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz),8.04 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s),10.45 (1H, s); ESIMS found for C₂₀H₂₃N₅O₂ m/z 366.0 (M+1).

2-(4-Ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 351

Beige solid (52.0 mg, 0.137 mmol, 52.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.03 (3H, br s), 2.30-2.47 (4H, m), 2.53-2.74 (6H, m),3.24 (2H, br s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H,d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s),9.96 (1H, br s); ESIMS found for C₂₁H₂₆N₆O m/z 379.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide352

Beige solid (66.0 mg, 0.162 mmol, 66.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.99 (6H, d, J=6.59 Hz), 2.51-2.54 (2H, m), 2.57 (4H, brs), 2.61-2.69 (1H, m), 3.20 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.64,1.51 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36 (1H, s), 8.43 (1H,s), 9.04 (1H, s), 9.89 (1H, s); ESIMS found for C₂₂H₂₈N₆O m/z 393.0(M+1).

2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 353

Beige solid (44.0 mg, 0.109 mmol, 44.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.26-0.32 (2H, m), 0.39-0.45 (2H, m), 1.66 (1H, tt,J=6.59, 3.43 Hz), 2.51-2.57 (4H, m), 2.62 (4H, br s), 3.20 (2H, s), 3.90(3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.78 Hz), 8.09(2H, s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMSfound for C₂₂H₂₆N₆O m/z 391.0 (M+1).

2-(4-(2-Fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 354

Off-white solid (33.0 mg, 0.083 mmol, 25.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.54 (4H, br s), 2.57-2.60 (3H, m), 2.64 (4H, dt,J=28.60, 4.95 Hz), 3.22 (2H, s), 3.90 (3H, s), 4.54 (2H, dt, J=47.80,4.70 Hz), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10(2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.93 (1H, s); ESIMSfound for C₂₁H₂₅FN₆O m/z 397.2 (M+1).

(S)-2-(2,4-Dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 355

Beige solid (20.0 mg, 0.053 mmol, 20.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.01 (3H, d, J=6.31 Hz), 1.87 (1H, br t, J=8.51 Hz),2.11-2.19 (1H, m), 2.17 (3H, s), 2.51-2.57 (1H, m), 2.57-2.67 (3H, m),2.83 (1H, dt, J=11.25, 3.02 Hz), 3.13 (1H, d, J=16.47 Hz), 3.43 (1H, d,J=16.74 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d,J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s), 8.43 (1H, s),9.04 (1H, s), 9.92 (1H, s); ESIMS found for C₂₁H₂₆N₆O m/z 379.2 (M+1).

1-(2-Hydroxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 358

White solid (41.0 mg, 0.108 mmol, 36.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.73 (2H, m), 1.73-1.81 (2H, m), 1.98 (2H, td,J=11.46, 2.06 Hz), 2.39 (2H, t, J=6.31 Hz), 2.52-2.57 (1H, m), 2.92 (2H,br d, J=11.53 Hz), 3.50 (2H, q, J=6.04 Hz), 3.90 (3H, s), 4.30 (1H, brt, J=5.35 Hz), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz),8.02 (1H, s), 8.06 (1H, s), 8.33 (1H, s), 8.44 (1H, s), 9.02 (1H, s),10.39 (1H, s); ESIMS found for C₂₁H₂₅N₅O₂ m/z 380.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide 359

Beige solid (11.0 mg, 0.026 mmol, 8.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.66-1.77 (2H, m), 1.77-1.84 (2H, m), 2.01-2.12 (2H, m), 2.53-2.62(1H, m), 2.85-2.94 (2H, m), 3.60 (2H, s), 3.90 (3H, s), 7.25 (1H, dd,J=6.86, 5.49 Hz), 7.46 (1H, d, J=7.96 Hz), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.77 (1H, td, J=7.62, 1.78 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H,s), 8.07 (1H, s), 8.33 (1H, s), 8.44 (1H, s), 8.49 (1H, br d, J=4.12Hz), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C₂₅H₂₆N₆O m/z 427.0(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide 360

White solid (65.0 mg, 0.156 mmol, 52.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.68 (2H, qd, J=12.21, 3.43 Hz), 1.79 (2H, br d, J=10.43Hz), 2.07-2.18 (2H, m), 2.51-2.57 (1H, m), 2.85-2.94 (2H, m), 3.67 (2H,s), 3.90 (3H, s), 7.17 (1H, d, J=0.82 Hz), 7.73 (1H, dd, J=8.64, 1.51Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.06 (1H, s), 8.06 (1H, d,J=0.82 Hz), 8.33 (1H, s), 8.43 (1H, s), 9.01 (1H, s), 10.40 (1H, s);ESIMS found for C₂₃H₂₄N₆O₂ m/z 416.95 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-carboxamide362

White solid (120.0 mg, 0.360 mmol, 57.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.70-1.83 (2H, m), 2.02 (1H, dtd, J=12.49, 8.16, 8.16,3.84 Hz), 2.08-2.18 (1H, m), 2.64 (1H, td, J=9.33, 6.86 Hz), 3.17 (1H,ddd, J=9.74, 6.17, 4.12 Hz), 3.90 (3H, s), 3.96 (1H, dd, J=9.06, 4.12Hz), 4.99-5.10 (2H, m), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.04 (1H, d,J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.38 (1H, s), 8.60 (1H, s), 9.09(1H, s); ESIMS found for C₁₉H₁₉N₅O m/z 334.1 (M+1).

(R)-1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide363

Off-white solid (65.0 mg, 0.194 mmol, 62.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.74-1.82 (2H, m), 1.82-1.90 (1H, m), 2.17-2.28 (1H, m),2.37-2.44 (1H, m), 2.42 (3H, s), 3.07 (1H, dd, J=9.88, 5.49 Hz), 3.17(1H, ddd, J=8.92, 6.04, 3.16 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.51,1.65 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.44 (1H,s), 9.03 (1H, s), 9.92 (1H, s); ESIMS found for C₁₉H₂₁N₅O m/z 336.2(M+1).

N-(4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide 364

Beige solid (240.0 mg, 0.734 mmol, 95.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.80-0.86 (4H, m), 1.91 (1H, quin, J=6.24 Hz), 3.92 (3H,s), 7.99 (1H, dd, J=8.51, 1.37 Hz), 8.14 (1H, s), 8.19 (1H, d, J=8.78Hz), 8.22 (1H, d, J=0.82 Hz), 8.49 (1H, s), 9.10 (1H, s), 10.48 (1H, s);ESIMS found for C₁₇H₁₅ClN₄O m/z 327.1 (M+1).

trans-4-Amino-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 365

Beige solid (350.0 mg, 1.00 mmol, 90.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.99-1.11 (2H, m), 1.42-1.64 (4H, m), 1.82 (4H, br d,J=11.80 Hz), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.35 (1H, s),8.42 (1H, s), 9.02 (1H, s), 10.40 (1H, s); ESIMS found for C₂₀H₂₃N₅O m/z350.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide366

White solid (260.0 mg, 0.736 mmol, 73.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53 (2H, qd, J=12.21, 3.98 Hz), 1.70 (2H, br d, J=10.98Hz), 2.42-2.49 (2H, m), 2.60-2.70 (1H, m), 2.97 (2H, br d, J=14.00 Hz),3.90 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.92 (1H, s), 8.11 (1H,s), 8.39 (1H, s), 8.49 (1H, s), 9.14 (1H, s), 10.56 (1H, s); ESIMS foundfor C₁₉H₂₀FN₅O m/z 354.15 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide367

Beige solid (15.0 mg, 0.037 mmol, 16.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.73-1.81(3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m),2.82-2.91 (2H, m), 3.90 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.92(1H, s), 8.11 (1H, s), 8.39 (1H, s), 8.49 (1H, s), 9.15 (1H, s), 10.61(1H, s); ESIMS found for C₂₃H₂₈FN₅O m/z 410.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide 368

Off-white solid (26.0 mg, 0.065 mmol, 28.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.68 (2H, qd, J=12.21, 3.70 Hz), 1.75-1.83 (2H, m),2.00-2.07 (2H, m), 2.52-2.57 (1H, m), 2.61 (2H, dt, J=28.30, 4.95 Hz),2.94 (2H, br d, J=11.53 Hz), 3.90 (3H, s), 4.53 (2H, dt, J=48.10, 5.25Hz), 7.59 (1H, dd, J=12.08, 1.37 Hz), 7.92 (1H, s), 8.11 (1H, d, J=0.82Hz), 8.39 (1H, s), 8.50 (1H, s), 9.15 (1H, s), 10.62 (1H, s); ESIMSfound for C₂₁H₂₃F₂N₅O m/z 400.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide369

Off-white solid (135.0 mg, 0.382 mmol, 74.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53 (2H, qd, J=12.17, 3.84 Hz), 1.70 (2H, br dd,J=12.08, 1.65 Hz), 2.43-2.49 (2H, m), 2.63 (1H, tt, J=11.63, 3.74 Hz),2.97 (2H, br d, J=12.08 Hz), 3.93 (3H, s), 7.89 (1H, d, J=11.80 Hz),8.10 (1H, s), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74 Hz), 8.49(1H, s), 9.03 (1H, s), 10.44 (1H, s); ESIMS found for C₁₉H₂₀FN₅O m/z354.15 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide370

Off-white solid (45.0 mg, 0.106 mmol, 53.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.73-1.81(3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.58 (1H, m),2.86 (2H, br d, J=11.25 Hz), 3.93 (3H, s), 7.89 (1H, d, J=11.53 Hz),8.10 (1H, d, J=0.82 Hz), 8.27 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74Hz), 8.50 (1H, s), 9.03 (1H, s), 10.49 (1H, s); ESIMS found forC₂₃H₂₈FN₅O m/z 410.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide 371

White solid (30.0 mg, 0.072 mmol, 51.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.68 (2H, qd, J=12.21, 3.70 Hz), 1.76-1.83 (2H, m), 2.04(2H, td, J=11.80, 2.20 Hz), 2.54 (1H, td, J=7.62, 3.98 Hz), 2.61 (2H,dt, J=28.35, 4.95 Hz), 2.94 (2H, br d, J=11.53 Hz), 3.93 (3H, s), 4.53(2H, dt, J=47.80, 4.95 Hz), 7.89 (1H, d, J=11.53 Hz), 8.10 (1H, s), 8.27(1H, d, J=7.68 Hz), 8.30 (1H, d, J=2.74 Hz), 8.50 (1H, s), 9.04 (1H, s),10.49 (1H, s); ESIMS found for C₂₁H₂₃F₂N₅O m/z 400.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide372

Off-white solid (16.0 mg, 0.042 mmol, 13.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 3.22 (2H,s), 3.93 (3H, s), 7.92 (1H, d, J=11.53 Hz), 8.13 (1H, s), 8.32 (1H, d,J=3.02 Hz), 8.34 (1H, d, J=7.41 Hz), 8.49 (1H, s), 9.05 (1H, s), 9.95(1H, s); ESIMS found for C₂₀H₂₃FN₆O m/z 383.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-fluorocyclopropane-1-carboxamide376

Beige solid (32.0 mg, 0.094 mmol, 19.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.33-1.42 (2H, m), 1.43-1.53 (2H, m), 2.39 (3H, s), 3.67(3H, s), 7.13 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s),8.13 (1H, d, J=8.51 Hz), 8.46 (1H, s), 9.18 (1H, s), 10.28 (1H, s);ESIMS found for C₁₈H₁₇FN₄O m/z 325.1 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide 433

Beige solid (14.0 mg, 0.048 mmol, 10.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.79-0.91 (4H, m), 2.03-2.12 (1H, m), 4.14 (3H, s), 8.01(1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.78 Hz), 8.26 (1H, s), 8.47(1H, s), 8.72 (1H, s), 9.12 (1H, s), 10.90 (1H, s); ESIMS found forC₁₆H₁₅N₅O m/z 294.1 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 441

White solid (57.8 mg, 0.156 mmol, 43.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67-1.91 (4H, m), 1.96 (2H, br d, J=12.90 Hz), 2.08-2.18(2H, m), 2.69-2.75 (1H, m), 4.14 (3H, s), 8.02 (1H, dd, J=8.51, 1.37Hz), 8.11 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.50 (1H, s), 8.73 (1H, s),9.12 (1H, s), 10.63 (1H, s); ESIMS found for C₉H₁₉F₂N₅O m/z 372.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide443

White solid (8.0 mg, 0.021 mmol, 10.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.13-1.23 (2H, m), 1.43-1.55 (2H, m), 1.83-1.96 (4H, m), 2.11-2.16(1H, m), 2.18 (6H, s), 2.44-2.48 (1H, m), 4.14 (3H, s), 8.01 (1H, dd,J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.49 (1H, s),8.72 (1H, s), 9.11 (1H, s), 10.47 (1H, s); ESIMS found for C₂₁H₂₆N₆O m/z379.2 (M+1).

trans-N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide448

Off-white solid (22.0 mg, 0.049 mmol, 14.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.82-0.95 (2H, m), 1.41-1.52 (3H, m), 1.79-1.91 (4H, m),2.08 (2H, d, J=7.14 Hz), 2.14 (3H, s), 2.31 (8H, br s), 2.51-2.55 (1H,m), 4.14 (3H, s), 8.00 (1H, dd, J=8.51, 1.37 Hz), 8.10 (1H, d, J=8.51Hz), 8.27 (1H, s), 8.50 (1H, s), 8.72 (1H, s), 9.10 (1H, s), 10.47 (1H,s); ESIMS found for C₂₅H₃₃N₇O m/z 448.3 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide452

White solid (119.4 mg, 0.355 mmol, 77.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.54 (2H, qd, J=12.17, 3.84 Hz), 1.71 (2H, br d, J=11.25Hz), 2.45-2.49 (2H, m), 2.65 (1H, tt, J=11.70, 3.67 Hz), 2.98 (2H, br d,J=12.08 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d,J=8.51 Hz), 8.28 (1H, s), 8.50 (1H, s), 8.73 (1H, s), 9.11 (1H, s),10.48 (1H, s); ESIMS found for C₁₈H₂₀N₆O m/z 337.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide470

White solid (75.9 mg, 0.166 mmol, 79.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.73 (2H, br s), 0.93-1.00 (2H, m), 1.63-1.74 (2H, m),1.78 (2H, br d, J=10.70 Hz), 1.95 (2H, brt, J=10.57 Hz), 2.52-2.60 (1H,m), 2.97 (2H, br d, J=10.98 Hz), 3.28 (2H, s), 4.14 (3H, s), 8.01 (1H,dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.50 (1H,s), 8.72 (1H, s), 9.11 (1H, s), 10.52 (1H, s); ESIMS found forC₂₃H₂₅F₃N₆O m/z 459.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide472

Beige solid (32.0 mg, 0.076 mmol, 21.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31 (3H, s), 1.60-1.71 (2H, m), 1.72-1.80 (2H, m),1.93-2.02 (2H, m), 2.48 (2H, br s), 2.52-2.59 (1H, m), 2.59-2.67 (2H,m), 4.14 (3H, s), 4.19 (2H, d, J=5.49 Hz), 4.36 (2H, d, J=5.76 Hz), 8.01(1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.50(1H, s), 8.73 (1H, s), 9.11 (1H, s), 10.54 (1H, s); ESIMS found forC₂₃H₂₈N₆O₂ m/z 421.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide 475

White solid (7.8 mg, 0.017 mmol, 20.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.44-1.55 (2H, m), 1.57-1.66 (2H, m), 1.67-1.73 (4H, m), 1.85 (2H,br d, J=10.43 Hz), 2.58-2.65 (1H, m), 2.82 (1H, ddd, J=11.32, 7.34, 4.39Hz), 2.99-3.06 (1H, m), 3.16-3.21 (2H, m), 3.30-3.38 (2H, m), 4.10 (1H,br d, J=1.10 Hz), 4.14 (3H, s), 4.36-4.44 (1H, m), 8.01 (1H, dd, J=8.51,1.37 Hz), 8.11 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.71 (1H,s), 9.11 (1H, s), 10.56 (1H, s); ESIMS found for C₂₄H₂₉N₇O₂ m/z 448.0(M+1).

1′-Methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide477

Off-white solid (65.0 mg, 0.150 mmol, 37.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.43 (2H, qd, J=11.94, 3.70 Hz), 1.57-1.70 (4H, m),1.75-1.86 (4H, m), 2.08-2.19 (1H, m), 2.12 (3H, s), 2.51-2.57 (1H, m),2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 3.17 (2H, d,J=2.20 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d,J=8.51 Hz), 8.28 (1H, s), 8.51 (1H, s), 8.72 (1H, s), 9.10 (1H, s),10.51 (1H, s); ESIMS found for C₂₄H₃₁N₇O m/z 434.25 (M+1).

(R)—N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide481

White solid (80.4 mg, 0.239 mmol, 87.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.36-1.46 (1H, m), 1.56-1.64 (1H, m), 1.64-1.72 (1H, m),1.84-1.92 (1H, m), 2.53-2.60 (1H, m), 2.63 (1H, dq, J=8.71, 4.41 Hz),2.75 (1H, dd, J=11.94, 8.92 Hz), 2.81 (1H, dt, J=12.14, 3.95 Hz), 3.00(1H, dd, J=11.94, 3.16 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.73 (1H, s),9.10 (1H, s), 10.81 (1H, s); ESIMS found for C₁₈H₂₀N₆O m/z 337.2 (M+1).

(R)-1-Isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 483

White solid (45.9 mg, 0.117 mmol, 82.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.88 (3H, d, J=6.59 Hz), 0.91 (3H, d, J=6.59 Hz),1.50-1.61 (2H, m), 1.65-1.73 (1H, m), 1.78-1.86 (2H, m), 2.08 (2H, br d,J=7.41 Hz), 2.10-2.16 (1H, m), 2.25-2.33 (1H, m), 2.55-2.62 (1H, m),2.77 (2H, br d, J=7.68 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65Hz), 8.11 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.73 (1H, s),9.10 (1H, s), 10.73 (1H, s); ESIMS found for C₂₂H₂₈N₆O m/z 393.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 487

Off-white solid (18.2 mg, 0.054 mmol, 16.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (4H, dt, J=6.52, 3.19 Hz), 2.62-2.70 (4H, m), 3.36(2H, s), 4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.37 Hz), 8.13 (1H, d,J=8.51 Hz), 8.34 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.12 (1H, s), 9.98(1H, s); ESIMS found for C₁₈H₂₀N₆O m/z 337.15 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide500

Beige solid (5.0 mg, 0.014 mmol, 4.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.19 (3H, s), 2.34-2.46 (4H, m), 2.58 (4H, br s), 3.23 (2H, s),4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.51 Hz),8.34 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.13 (1H, s), 10.00 (1H, s);ESIMS found for C₁₉H₂₃N₇O m/z 366.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide 513

White solid (12.2 mg, 0.034 mmol, 17.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34 (4H, br d, J=7.14 Hz), 1.75 (4H, br d, J=6.86 Hz),3.20 (2H, s), 3.37 (2H, br s), 4.14 (3H, s), 8.05 (1H, dd, J=8.51, 1.37Hz), 8.14 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.52 (1H, s), 8.74 (1H, s),9.12 (1H, s), 10.14 (1H, s); ESIMS found for C₂₀H₂₂N₆O m/z 363.2 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)propanamide 517

Off-white solid (70.0 mg, 0.224 mmol, 50.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64 (6H, d, J=21.70 Hz), 3.83 (3H, s), 7.32 (1H, d,J=1.10 Hz), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.07 (1H, s),8.14 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.18 (1H, s), 9.85 (1H, br d,J=3.57 Hz); ESIMS found for C₁₇H₁₇FN₄O m/z 313.0 (M+1).

1-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide521

White solid (100.0 mg, 0.306 mmol, 63.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34-1.42 (2H, m), 1.42-1.52 (2H, m), 3.83 (3H, s), 7.38(1H, br s), 7.73 (1H, br d, J=8.51 Hz), 7.86 (1H, br s), 8.06 (1H, s),8.14 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.19 (1H, s), 10.29 (1H, s);ESIMS found for C₁₇H₁₅FN₄O m/z 311.1 (M+1).

2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide523

White solid (5.0 mg, 0.014 mmol, 7.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.15 (3H, s), 2.22-2.36 (4H, m), 3.04 (2H, s), 3.14 (2H, s),3.22-3.29 (1H, m), 3.83 (3H, s), 7.30 (1H, d, J=1.10 Hz), 7.66 (1H, dd,J=8.51, 1.65 Hz), 7.79 (1H, s), 8.00 (1H, s), 8.08 (1H, d, J=8.51 Hz),8.54 (1H, s), 9.11 (1H, s), 10.42 (1H, s); ESIMS found for C₂₁H₂₃N₅O m/z362.2 (M+1).

1-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide527

White solid (16.0 mg, 0.043 mmol, 10.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30-1.42 (1H, m), 1.50-1.63 (2H, m), 1.68 (3H, br d,J=9.61 Hz), 1.85-2.02 (4H, m), 3.84 (3H, s), 7.32 (1H, d, J=1.10 Hz),7.73 (1H, dd, J=8.51, 1.92 Hz), 7.80 (1H, s), 8.07 (1H, s), 8.13 (1H, d,J=8.51 Hz), 8.50 (1H, s), 9.17 (1H, s), 9.83 (1H, d, J=4.12 Hz); ESIMSfound for C₂₀H₂₁FN₄O m/z 353.15 (M+1).

trans-4-Methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 528

White solid (96.6 mg, 0.265 mmol, 39.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.06-1.18 (2H, m), 1.44-1.56 (2H, m), 1.86-1.95 (2H, m),2.04-2.12 (2H, m), 2.52-2.58 (1H, m), 3.07-3.16 (1H, m), 3.25 (3H, s),3.82 (3H, s), 7.30 (1H, s), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H,s), 7.99 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.12 (1H, s),10.50 (1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.2 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide531

Off-white solid (17.0 mg, 0.047 mmol, 7.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.95 (2H, qd, J=12.81, 3.29 Hz), 1.36 (1H, dtt, J=14.75,5.90, 5.90, 3.05, 3.05 Hz), 1.45 (2H, qd, J=12.76, 3.16 Hz), 1.80 (2H,br dd, J=13.04, 2.61 Hz), 1.84-1.93 (2H, m), 2.51-2.54 (1H, m), 3.24(2H, t, J=5.76 Hz), 3.82 (3H, s), 4.38 (1H, t, J=5.35 Hz), 7.30 (1H, d,J=1.10 Hz), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 7.98 (1H, d,J=0.82 Hz), 8.08 (1H, d, J=8.51 Hz), 8.53 (1H, s), 9.12 (1H, s), 10.47(1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide535

Orange solid (4.0 mg, 0.013 mmol, 3.5% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 3.23-3.32 (1H, m), 3.70-3.78 (2H, m), 3.83 (3H, s), 3.90-3.98 (2H,m), 7.31 (1H, d, J=1.10 Hz), 7.69 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H,s), 8.03 (1H, s), 8.10 (1H, d, J=8.51 Hz), 8.57 (1H, s), 9.13 (1H, s),10.65 (1H, br s) ESIMS found for C₁₇H₁₇N₅O m/z 308.15 (M+1).

(R)—N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide537

Off-white solid (100.0 mg, 0.310 mmol, 69.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.84-1.97 (2H, m), 1.98-2.08 (1H, m), 2.20-2.31 (1H, m),3.83 (3H, s), 3.84-3.90 (1H, m), 4.00-4.07 (1H, m), 4.54 (1H, dd,J=8.23, 5.76 Hz), 7.31 (1H, d, J=0.82 Hz), 7.70 (1H, dd, J=8.51, 1.65Hz), 7.79 (1H, s), 8.05 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.52 (1H, s),9.14 (1H, s), 9.79 (1H, s); ESIMS found for C₁₈H₁₈N₄O₂ m/z 323.0 (M+1).

1-(2-Methoxyethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 547

Yellow-white solid (5.0 mg, 0.013 mmol, 8.5% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 1.88-1.98 (4H, m), 2.25 (2H, dt, J=11.05, 7.51 Hz),2.56 (1H, dt, J=15.51, 7.62 Hz), 2.66 (2H, t, J=5.63 Hz), 3.12 (2H, brd, J=11.80 Hz), 3.36 (3H, s), 3.57 (2H, t, J=5.63 Hz), 3.85 (3H, s),7.28 (1H, s), 7.64 (1H, dd, J=8.51, 1.65 Hz), 7.85 (1H, s), 7.94 (1H,s), 8.07 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.06 (1H, s); ESIMS found forC₂₂H₂₇N₅O₂ m/z 394.2 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide554

White solid (50.0 mg, 0.121 mmol, 31.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.85 (6H, d, J=6.59 Hz), 1.60-1.73 (2H, m), 1.74-1.81(3H, m), 1.83-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.60 (1H, m),2.86 (2H, br d, J=11.25 Hz), 3.83 (3H, s), 7.30 (1H, d, J=1.10 Hz), 7.66(1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.00 (1H, s), 8.08 (1H, d,J=8.78 Hz), 8.54 (1H, s), 9.12 (1H, s), 10.52 (1H, s); ESIMS found forC₂₃H₂₉N₅O m/z 392.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide 561

Beige solid (15.0 mg, 0.036 mmol, 21.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64-1.77 (2H, m), 1.91-1.98 (2H, m), 2.65-2.73 (1H, m),2.77 (2H, td, J=11.94, 2.20 Hz), 2.89 (3H, s), 3.59-3.67 (2H, m), 3.83(3H, s), 7.30 (1H, d, J=1.10 Hz), 7.67 (1H, dd, J=8.64, 1.51 Hz), 7.78(1H, s), 8.01 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.54 (1H, s), 9.13 (1H,s), 10.62 (1H, s); ESIMS found for C₂₀H₂₃N₅O₃S m/z 413.9 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide 579

White solid (15.0 mg, 0.043 mmol, 10.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.69 (4H,m), 3.28-3.31 (1H, m), 3.83 (3H, s), 7.31 (1H, s), 7.69 (1H, dd, J=8.51,1.65 Hz), 7.80 (1H, s), 8.04 (1H, s), 8.10 (1H, d, J=8.51 Hz), 8.53 (1H,s), 9.13 (1H, s), 10.02 (1H, s); ESIMS found for C₂₀H₂₃N₅O m/z 350.2(M+1).

N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide643

Brown solid (31.0 mg, 0.082 mmol, 32.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.80(3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m),2.86 (2H, br d, J=11.25 Hz), 7.80 (1H, dd, J=8.64, 1.51 Hz), 7.99 (1H,d, J=8.51 Hz), 8.09 (1H, s), 8.14 (1H, br s), 8.42 (1H, br s), 8.45 (1H,s), 9.02 (1H, s), 10.44 (1H, s), 13.09 (1H, br s); ESIMS found forC₂₂H₂₇N₅O m/z 378.2 (M+1).

3,3-Difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide699

Beige solid (8.0 mg, 0.023 mmol, 8.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.75-2.90 (5H, m), 7.89 (1H, dd, J=8.64, 1.78 Hz), 8.12 (1H, d,J=8.51 Hz), 8.24 (1H, s), 8.56 (1H, s), 8.57 (1H, s), 9.14 (1H, s), 9.20(1H, s), 10.82 (1H, s); ESIMS found for C₁₇H₁₃F₂N₃OS m/z 346.05 (M+1).

2-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide700

Beige solid (4.0 mg, 0.011 mmol, 12.8% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 2.39 (3H, s), 2.42-2.55 (4H, m), 3.22-3.29 (1H, m),3.41 (2H, s), 3.48 (2H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.05 (1H, d,J=8.51 Hz), 8.11 (1H, d, J=0.82 Hz), 8.40 (1H, s), 8.50 (1H, s), 9.02(1H, s), 9.06 (1H, s); ESIMS found for C₂₀H₂₀N₄OS m/z 365.1 (M+1).

1-Fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide704

Light pink solid (14.0 mg, 0.039 mmol, 17.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.28-1.42 (1H, m), 1.49-1.62 (2H, m), 1.68 (3H, br d,J=9.61 Hz), 1.85-2.02 (4H, m), 7.93 (1H, dd, J=8.64, 1.78 Hz), 8.15 (1H,d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.58 (1H, s), 9.18 (1H, s),9.20 (1H, s), 9.87 (1H, d, J=4.12 Hz); ESIMS found for C₁₉H₁₈FN₃OS m/z355.9 (M+1).

trans-4-(Dimethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide707

White solid (48.0 mg, 0.126 mmol, 25.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.12-1.22 (2H, m), 1.42-1.54 (2H, m), 1.83-1.97 (4H, m),2.11-2.16 (1H, m), 2.18 (6H, s), 2.43-2.49 (1H, m), 7.85 (1H, dd,J=8.64, 1.51 Hz), 8.10 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s),8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.49 (1H, s); ESIMS found forC₂₁H₂₄N₄OS m/z 381.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide711

Beige solid (22.0 mg, 0.052 mmol, 21.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.84-0.97 (2H, m), 1.21-1.33 (1H, m), 1.44 (2H, qd,J=12.76, 2.88 Hz), 1.80 (2H, br dd, J=12.76, 2.33 Hz), 1.86 (2H, br d,J=10.70 Hz), 2.29 (2H, d, J=6.86 Hz), 2.45-2.49 (1H, m), 2.97-3.08 (2H,m), 3.48-3.60 (2H, m), 5.12 (1H, dq, J=58.00, 5.20 Hz), 7.86 (1H, dd,J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s),8.56 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.49 (1H, s); ESIMS found forC₂₃H₂₅FN₄OS m/z 425.2 (M+1).

N-(6-(Thiazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide 713

Orange solid (6.0 mg, 0.019 mmol, 8.4% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 3.70 (2H, br t, J=7.96 Hz), 3.82 (1H, dt, J=15.09, 7.55 Hz),3.87-3.93 (2H, m), 7.88 (1H, dd, J=8.51, 1.92 Hz), 8.11 (1H, d, J=8.51Hz), 8.24 (1H, s), 8.57 (1H, br s), 8.57 (1H, s), 9.13 (1H, s), 9.20(1H, s), 10.65 (1H, br s); ESIMS found for C₁₆H₁₄N₄OS m/z 311.1 (M+1).

1-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide718

Beige solid (16.0 mg, 0.045 mmol, 21.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 1.87 (2H, td,J=11.53, 1.92 Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.81 (2H, br d,J=11.25 Hz), 7.86 (1H, dd, J=8.64, 1.51 Hz), 8.10 (1H, d, J=8.51 Hz),8.20 (1H, s), 8.53 (1H, s), 8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s),10.54 (1H, s); ESIMS found for C₁₉H₂₀N₄OS m/z 352.9 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide731

White solid (54.3 mg, 0.131 mmol, 52.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63 (3H, t, J=19.07 Hz), 1.68-1.75 (2H, m), 1.75-1.81(2H, m), 2.22 (2H, td, J=11.66, 2.47 Hz), 2.51-2.60 (1H, m), 2.71 (2H,t, J=14.00 Hz), 2.95 (2H, br d, J=11.53 Hz), 7.86 (1H, dd, J=8.64, 1.78Hz), 8.10 (1H, d, J=8.78 Hz), 8.21 (1H, d, J=0.82 Hz), 8.53 (1H, s),8.56 (1H, s), 9.13 (1H, s), 9.19 (1H, s), 10.56 (1H, s); ESIMS found forC₂₁H₂₂F₂N₄OS m/z 417.2 (M+1).

1-(Oxetan-3-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide737

White solid (39.0 mg, 0.099 mmol, 42.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64-1.73 (2H, m), 1.75-1.85 (4H, m), 2.53-2.61 (1H, m),2.71-2.78 (2H, m), 3.35-3.41 (1H, m), 4.43 (2H, t, J=6.17 Hz), 4.53 (2H,t, J=6.45 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz),8.21 (1H, d, J=1.10 Hz), 8.55 (1H, s), 8.56 (1H, s), 9.12 (1H, s), 9.19(1H, s), 10.56 (1H, s) ESIMS found for C₂₁H₂₂N₄O₂S m/z 395.1 (M+1).

1-(2-(Pyrrolidin-1-yl)acetyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide741

White solid (124.6 mg, 0.277 mmol, 69.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.42-1.55 (1H, m), 1.57-1.68 (1H, m), 1.72 (4H, br s),1.85 (2H, br d, J=10.98 Hz), 2.55 (4H, br s), 2.58-2.67 (1H, m),2.78-2.88 (1H, m), 3.03 (1H, br t, J=11.94 Hz), 3.25-3.30 (1H, m), 3.44(1H, br d, J=13.17 Hz), 4.07 (1H, br d, J=14.00 Hz), 4.40 (1H, br d,J=12.62 Hz), 7.87 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.78 Hz),8.21 (1H, s), 8.53 (1H, s), 8.56 (1H, s), 9.13 (1H, s), 9.19 (1H, s),10.64 (1H, s); ESIMS found for C₂₄H₂₇N₅O₂S m/z 449.9 (M+1).

1′-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide743

Beige solid (55.0 mg, 0.126 mmol, 36.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (2H, qd, J=11.94, 3.70 Hz), 1.58-1.71 (4H, m),1.75-1.87 (4H, m), 2.09-2.20 (3H, m), 2.12 (3H, s), 2.51-2.57 (1H, m),2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 7.86 (1H, dd,J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.54 (1H, s),8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.52 (1H, s); ESIMS found forC₂₄H₂₉N₅OS m/z 436.2 (M+1).

2-(Pyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide 758

Beige solid (40.0 mg, 0.114 mmol, 26.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.68 (4H,m), 3.27-3.34 (1H, m), 7.88 (1H, dd, J=8.64, 1.78 Hz), 8.12 (1H, d,J=8.78 Hz), 8.25 (1H, d, J=0.82 Hz), 8.53 (1H, s), 8.57 (1H, s), 9.13(1H, s), 9.20 (1H, s), 10.04 (1H, s); ESIMS found for C₁₉H₂₀N₄OS m/z353.2 (M+1).

2-(Piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 760

Yellow-white solid (8.0 mg, 0.023 mmol, 16.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.40-1.48 (2H, m), 1.59 (4H, dt, J=11.05, 5.59 Hz),2.51-2.57 (4H, m), 3.18 (2H, s), 7.89 (1H, dd, J=8.51, 1.92 Hz), 8.13(1H, d, J=8.51 Hz), 8.27 (1H, d, J=1.10 Hz), 8.53 (1H, s), 8.58 (1H, d,J=0.82 Hz), 9.14 (1H, s), 9.20 (1H, s), 9.99 (1H, s); ESIMS found forC₁₉H₂₀N₄OS m/z 353.1 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide767

Beige solid (10.0 mg, 0.027 mmol, 8.2% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.59 (4H, br s), 3.23 (2H, s), 7.89(1H, dd, J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.53(1H, s), 8.58 (1H, s), 9.14 (1H, s), 9.20 (1H, s), 10.02 (1H, s); ESIMSfound for C₁₉H₂₁N₅OS m/z 368.0 (M+1).

2-Morpholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 773

Pale green solid (43.0 mg, 0.121 mmol, 42.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.54-2.62 (4H, m), 3.26 (2H, s), 3.62-3.69 (4H, m), 7.89(1H, dd, J=8.64, 1.78 Hz), 8.13 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53(1H, s), 8.58 (1H, s), 9.15 (1H, s), 9.20 (1H, s), 10.10 (1H, s); ESIMSfound for C₁₈H₁₈N₄O₂S m/z 355.1 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)propanamide784

Beige solid (40.0 mg, 0.098 mmol, 36.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.38 (2H, br d, J=3.29 Hz), 1.49 (4H, quin, J=5.21 Hz),1.64 (6H, d, J=22.00 Hz), 2.37 (4H, br s), 3.65 (2H, s), 3.92 (3H, s),7.76 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.08 (1H, d, J=8.51 Hz),8.13 (1H, s), 8.42 (1H, s), 9.13 (1H, s), 9.85 (1H, d, J=3.84 Hz); ESIMSfound for C₂₃H₂₈FN₅O m/z 410.2 (M+1).

2-(Diethylamino)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 785

Orange gum (200.0 mg, 0.460 mmol, 60.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.05 (6H, t, J=7.14 Hz), 1.34-1.42 (2H, m), 1.44-1.54(4H, m), 2.36 (4H, br s), 2.64 (4H, q, J=6.95 Hz), 3.24 (2H, s), 3.64(2H, s), 3.91 (3H, s), 7.72 (1H, dd, J=8.37, 1.51 Hz), 7.81 (1H, s),8.04 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.45 (1H, s), 9.08 (1H, s), 9.93(1H, s); ESIMS found for C₂₅H₃₄N₆O m/z 435.3 (M+1).

2-(2-Fluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 791

White solid (20.0 mg, 0.041 mmol, 23.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.38 (2H, br d, J=3.57 Hz), 1.45-1.54 (4H, m), 2.24-2.33(4H, m), 2.36 (4H, br s), 2.60 (2H, dt, J=28.60, 4.95 Hz), 3.12 (2H, s),3.22 (2H, s), 3.27 (1H, t, J=8.37 Hz), 3.65 (2H, s), 3.91 (3H, s), 4.36(2H, dt, J=47.80, 4.95 Hz), 7.69 (1H, dd, J=8.51, 1.37 Hz), 7.80 (1H,s), 8.02 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.46 (1H, s), 9.06 (1H, s),10.39 (1H, s); ESIMS found for C₂₈H₃₅FN₆O m/z 491.3 (M+1).

trans-4-Methoxy-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide795

White solid (33.7 mg, 0.073 mmol, 54.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.07-1.18 (2H, m), 1.38 (2H, br d, J=3.29 Hz), 1.43-1.52(6H, m), 1.89 (2H, br d, J=11.53 Hz), 2.04-2.12 (2H, m), 2.36 (4H, brs), 2.51-2.57 (1H, m), 3.12 (1H, tt, J=10.67, 4.15 Hz), 3.25 (3H, s),3.64 (2H, s), 3.91 (3H, s), 7.69 (1H, dd, J=8.37, 1.51 Hz), 7.80 (1H,s), 8.02 (1H, d, J=8.51 Hz), 8.04 (1H, br s), 8.45 (1H, s), 9.07 (1H,s), 10.46 (1H, s); ESIMS found for C₂₇H₃₅N₅O₂ m/z 462.3 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide798

White solid (50.6 mg, 0.110 mmol, 103% yield). ¹¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.90-1.01 (2H, m), 1.32-1.42 (4H, m), 1.42-1.53 (6H, m),1.80 (2H, br dd, J=13.04, 2.61 Hz), 1.85-1.91 (2H, m), 2.36 (4H, br s),3.24 (2H, t, J=5.63 Hz), 3.64 (2H, s), 3.91 (3H, s), 4.39 (1H, t, J=5.21Hz), 7.68 (1H, dd, J=8.37, 1.51 Hz), 7.80 (1H, s), 8.00-8.06 (2H, m),8.46 (1H, s), 9.07 (1H, s), 10.42 (1H, s); ESIMS found for C₂₇H₃₅N₅O₂m/z 462.3 (M+1).

(R)—N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide803

Off-white solid (40.0 mg, 0.096 mmol, 58.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.38 (2H, br s), 1.46-1.52 (4H, m), 1.67 (2H, quin,J=6.79 Hz), 1.80-1.89 (1H, m), 2.05-2.15 (1H, m), 2.36 (4H, br s), 2.87(1H, dt, J=10.15, 6.31 Hz), 2.97 (1H, dt, J=10.15, 6.72 Hz), 3.64 (2H,s), 3.80 (1H, dd, J=9.06, 5.49 Hz), 3.91 (3H, s), 7.71 (1H, dd, J=8.51,1.65 Hz), 7.81 (1H, s), 8.04 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.46 (1H,s), 9.07 (1H, s), 10.36 (1H, s); ESIMS found for C₂₄H₃₀N₆O m/z 419.3(M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide826

Off-white solid (40.0 mg, 0.082 mmol, 27.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34-1.42 (2H, m), 1.44-1.53 (4H, m), 1.63-1.73 (2H, m),1.74-1.86 (4H, m), 2.36 (4H, br s), 2.53-2.61 (1H, m), 2.71-2.82 (2H,m), 3.40 (1H, br s), 3.65 (2H, br s), 3.91 (3H, s), 4.44 (2H, br t,J=5.90 Hz), 4.50-4.57 (2H, m), 7.69 (1H, dd, J=8.64, 1.51 Hz), 7.79 (1H,s), 7.99-8.06 (2H, m), 8.47 (1H, s), 9.07 (1H, s), 10.48 (1H, s); ESIMSfound for C₂₈H₃₆N₆O₂ m/z 489.3 (M+1).

1-Benzoyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 831

White solid (53.0 mg, 0.099 mmol, 58.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.38 (2H, br d, J=3.02 Hz), 1.45-1.54 (4H, m), 1.57-1.71(2H, m), 1.74-1.86 (1H, m), 1.89-1.98 (1H, m), 2.36 (4H, br s),2.45-2.49 (1H, m), 2.86 (2H, ddt, J=11.25, 7.55, 3.77, 3.77 Hz),3.02-3.16 (1H, m), 3.65 (2H, s), 3.91 (3H, s), 4.46-4.61 (1H, m),7.37-7.43 (2H, m), 7.43-7.49 (3H, m), 7.70 (1H, dd, J=8.51, 1.37 Hz),7.80 (1H, s), 8.03 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.46 (1H, s), 9.08(1H, s), 10.58 (1H, s); ESIMS found for C₃₂H₃₆N₆O₂ m/z 537.3 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 839

White amorphous solid (25.8 mg, 0.060 mmol, 69.3% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.35-1.41 (2H, m), 1.46-1.52 (4H, m), 1.66-1.77 (4H,m), 2.36 (4H, br d, J=1.65 Hz), 2.77-2.88 (1H, m), 3.33-3.39 (2H, m),3.65 (2H, s), 3.89-3.94 (2H, m), 3.91 (3H, s), 7.66-7.73 (1H, m), 7.80(1H, s), 8.00-8.06 (2H, m), 8.46 (1H, s), 9.08 (1H, s), 10.52 (1H, s);ESIMS found for C₂₅H₃₁N₅O₂ m/z 434.2 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide851

Off-white solid (180.0 mg, 0.391 mmol, 54.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.93 (3H, d, J=6.31 Hz), 1.20-1.30 (2H, m), 1.33-1.42(3H, m), 1.44-1.53 (4H, m), 1.63 (2H, br d, J=11.53 Hz), 2.16-2.24 (2H,m), 2.36 (4H, br s), 2.87 (2H, br d, J=11.53 Hz), 3.18 (2H, s), 3.65(2H, s), 3.91 (3H, s), 7.72 (1H, dd, J=8.51, 1.37 Hz), 7.82 (1H, s),8.05 (1H, d, J=8.78 Hz), 8.12 (1H, s), 8.45 (1H, s), 9.08 (1H, s), 9.91(1H, s); ESIMS found for C₂₇H₃₆N₆O m/z 461.3 (M+1).

1-Fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide883

Off-white solid (36.5 mg, 0.099 mmol, 63.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31-1.40 (1H, m), 1.51-1.62 (2H, m), 1.69 (3H, br d,J=9.33 Hz), 1.87-2.02 (4H, m), 2.83 (3H, s), 8.15 (1H, dd, J=8.51, 1.65Hz), 8.24 (1H, d, J=8.51 Hz), 8.53 (1H, s), 8.58 (1H, s), 9.27 (1H, s),9.97 (1H, d, J=3.84 Hz); ESIMS found for C₁₉H₁₉FN₄OS m/z 371.1 (M+1).

trans-4-Methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 885

White solid (33.4 mg, 0.087 mmol, 21.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.08-1.19 (2H, m), 1.44-1.56 (2H, m), 1.88-1.94 (2H, m),2.05-2.13 (2H, m), 2.52-2.58 (1H, m), 2.83 (3H, s), 3.09-3.17 (1H, m),3.25 (3H, s), 8.09 (1H, dd, J=8.65, 1.51 Hz), 8.19 (1H, d, J=8.51 Hz),8.44 (1H, s), 8.60 (1H, s), 9.21 (1H, s), 10.60 (1H, s); ESIMS found forC₂₀H₂₂N₄O₂S m/z 383.15 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide888

White solid (12.4 mg, 0.032 mmol, 39.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.90-1.02 (2H, m), 1.30-1.40 (1H, m), 1.46 (2H, qd,J=12.76, 3.43 Hz), 1.81 (2H, br dd, J=13.04, 2.61 Hz), 1.86-1.93 (2H,m), 2.52-2.56 (1H, m), 2.83 (3H, s), 3.24 (2H, t, J=5.76 Hz), 4.39 (1H,t, J=5.35 Hz), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz),8.43 (1H, s), 8.61 (1H, s), 9.21 (1H, s), 10.57 (1H, s); ESIMS found forC₂₀H₂₂N₄O₂S m/z 383.1 (M+1).

1-(2-Fluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 900

Beige solid (41.0 mg, 0.103 mmol, 19.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.69 (2H, qd, J=12.12, 3.70 Hz), 1.76-1.85 (2H, m),2.02-2.09 (2H, m), 2.52-2.57 (1H, m), 2.62 (2H, dt, J=28.35, 4.95 Hz),2.83 (3H, s), 2.95 (2H, br d, J=11.53 Hz), 4.54 (2H, dt, J=47.80, 4.95Hz), 8.09 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H,s), 8.63 (1H, s), 9.21 (1H, s), 10.62 (1H, s); ESIMS found forC₂₀H₂₂FN₅OS m/z 400.15 (M+1).

1-Benzoyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide921

Off-white solid (78.5 mg, 0.172 mmol, 42.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64 (2H, br s), 1.77-1.89 (1H, m), 1.90-2.04 (1H, m),2.78-2.92 (2H, m), 2.83 (3H, s), 3.10 (1H, tdd, J=5.01, 5.01, 2.88, 1.37Hz), 3.58-3.76 (1H, m), 4.42-4.61 (1H, m), 7.37-7.43 (2H, m), 7.43-7.49(3H, m), 8.10 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.46(1H, d, J=0.82 Hz), 8.62 (1H, s), 9.22 (1H, s), 10.72 (1H, s); ESIMSfound for C₂₅H₂₃N₅O₅₂S m/z 458.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 932

Beige solid (46.0 mg, 0.130 mmol, 21.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (7H, dt, J=6.86, 3.16 Hz), 2.62-2.70 (4H, m), 2.83(3H, s), 3.38 (2H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d,J=8.51 Hz), 8.50 (1H, s), 8.61 (1H, s), 9.22 (1H, s), 10.08 (1H, s);ESIMS found for C₁₈H₁₉N₅OS m/z 354.1 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 939

Beige solid (77.0 mg, 0.210 mmol, 21.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.39-1.47 (2H, m), 1.59 (4H, quin, J=5.56 Hz), 2.52-2.57(4H, m), 2.83 (3H, s), 3.19 (2H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz),8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.61 (1H, s), 9.22 (1H, s), 10.06(1H, s); ESIMS found for C₁₉H₂₁N₅OS m/z 368.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide946

Beige solid (11.0 mg, 0.029 mmol, 8.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.59 (4H, br s), 2.83 (3H, s), 3.24(2H, s), 8.12 (1H, dd, J=8.78, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51(1H, s), 8.61 (1H, s), 9.23 (1H, s), 10.09 (1H, s); ESIMS found forC₁₉H₂₂N₆OS m/z 383.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide952

Pale yellow solid (11.0 mg, 0.030 mmol, 9.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.61 (4H, m), 2.83 (3H, s), 3.27 (2H, s), 3.62-3.70(4H, m), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.78 Hz), 8.51(1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.17 (1H, s); ESIMS found forC₁₈H₁₉N₅O₂S m/z 370.1 (M+1).

(R)—N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide953

Beige solid (66.0 mg, 0.172 mmol, 23.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.96 (3H, d, J=6.31 Hz), 2.54-2.60 (1H, m), 2.63 (1H,ddd, J=9.06, 6.17, 2.88 Hz), 2.80-2.82 (1H, m), 2.83 (3H, s), 3.19 (1H,dd, J=11.11, 8.92 Hz), 3.21 (1H, d, J=16.47 Hz), 3.49 (1H, d, J=16.47Hz), 3.54-3.62 (1H, m), 3.68 (1H, dd, J=11.25, 3.02 Hz), 3.71-3.79 (1H,m), 8.08-8.18 (1H, m), 8.22 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62 (1H,s), 9.23 (1H, s), 10.13 (1H, s); ESIMS found for C₁₉H₂₁N₅O₂S m/z 384.2(M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide 959

Beige solid (27.0 mg, 0.071 mmol, 18.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34 (4H, d, J=7.14 Hz), 1.71-1.79 (4H, m), 2.83 (3H, s),3.21 (2H, s), 3.35-3.40 (2H, m), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.22(1H, d, J=8.51 Hz), 8.52 (1H, s), 8.63 (1H, s), 9.22 (1H, s), 10.21 (1H,s); ESIMS found for C₂₀H₂₁N₅OS m/z 380.1 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide960

Off-white solid (110.0 mg, 0.288 mmol, 47.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67 (1H, dd, J=9.74, 0.96 Hz), 1.87 (1H, dd, J=9.74,1.78 Hz), 2.63 (1H, d, J=9.88 Hz), 2.83 (3H, s), 2.96 (1H, dd, J=9.88,1.65 Hz), 3.48 (2H, d, J=4.94 Hz), 3.59 (1H, dd, J=7.68, 1.65 Hz), 3.64(1H, s), 3.88 (1H, d, J=7.41 Hz), 4.41 (1H, s), 8.12 (1H, dd, J=8.51,1.65 Hz), 8.22 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H,s), 10.07 (1H, s); ESIMS found for C₁₉H₁₉N₅O₂S m/z 382.1 (M+1).

2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide962

Off-white solid (175.0 mg, 0.065 mmol, 17.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76-1.82 (2H, m), 1.87-1.94 (2H, m), 2.83 (3H, s), 3.16(2H, s), 3.18 (2H, br d, J=1.10 Hz), 3.52 (2H, dd, J=10.57, 1.51 Hz),3.68 (2H, d, J=10.43 Hz), 8.13 (1H, dd, J=8.51, 1.65 Hz), 8.22 (1H, d,J=8.78 Hz), 8.52 (1H, s), 8.63 (1H, s), 9.25 (1H, s), 10.28 (1H, s);ESIMS found for C₂₀H₂₁N₅O₂S m/z 396.15 (M+1).

N-(8-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide963

Beige solid (25.0 mg, 0.065 mmol, 17.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.63 (4H, m), 2.83 (3H, s), 3.28 (2H, s), 3.61-3.69(4H, m), 7.89 (1H, dd, J=11.11, 1.24 Hz), 8.40 (1H, s), 8.68 (1H, s),9.34 (1H, s), 10.32 (1H, s); ESIMS found for C₁₈H₁₈FN₅O₂S m/z 388.1(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(phenylsulfonyl)piperidine-4-carboxamide 964

White solid (81.0 mg, 0.170 mmol, 63.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.75 (2H, m), 1.90 (2H, br dd, J=13.58, 2.88 Hz),2.27-2.36 (2H, m), 2.51-2.56 (1H, m), 3.69 (2H, br d, J=12.08 Hz), 3.90(3H, s), 7.65-7.70 (2H, m), 7.72-7.80 (4H, m), 7.99 (1H, d, J=8.51 Hz),8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.39 (1H, s), 9.01 (1H, s),10.45 (1H, s); ESIMS found for C₂₅H₂₅N₅O₃S m/z 475.9 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d3)piperazin-1-yl)acetamide 965

Beige solid (70.0 mg, 0.191 mmol, 28.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (4H, br s), 2.58 (4H, br s), 3.22 (2H, s), 3.90 (3H,s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H,s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS foundfor C₂₀H₂₁[²H₃]N₆O m/z 368.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide966

White solid (65.0 mg, 0.177 mmol, 80.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.72 (2H, m), 1.73-1.80 (2H, m), 1.86 (2H, td,J=11.66, 2.20 Hz), 2.16 (3H, s), 2.45-2.55 (1H, m), 2.76-2.85 (2H, m),3.93 (3H, s), 7.89 (1H, d, J=11.80 Hz), 8.10 (1H, s), 8.26 (1H, d,J=7.41 Hz), 8.30 (1H, d, J=2.74 Hz), 8.49 (1H, s), 9.03 (1H, s), 10.49(1H, s); ESIMS found for C₂₀H₂₂FN₅O m/z 368.2 (M+1).

1-Ethyl-N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 967

White solid (20.0 mg, 0.052 mmol, 26.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.00 (3H, t, J=7.14 Hz), 1.67 (2H, td, J=12.21, 3.57 Hz),1.75-1.81 (2H, m), 1.86 (2H, td, J=11.73, 2.06 Hz), 2.31 (2H, q, J=7.14Hz), 2.51-2.58 (1H, m), 2.87-2.95 (2H, m), 3.93 (3H, s), 7.89 (1H, d,J=11.53 Hz), 8.10 (1H, d, J=0.82 Hz), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H,d, J=2.47 Hz), 8.50 (1H, s), 9.03 (1H, s), 10.49 (1H, s); ESIMS foundfor C₂₁H₂₄FN₅O m/z 382.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide968

Beige solid (25.0 mg, 0.065 mmol, 23.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.33 (3H, br s), 2.52-2.77 (8H, m), 3.27 (2H, s), 3.90(3H, s), 7.62 (1H, dd, J=12.08, 1.37 Hz), 7.99 (1H, s), 8.14 (1H, d,J=0.82 Hz), 8.41 (1H, s), 8.48 (1H, s), 9.17 (1H, s), 10.12 (1H, br s);ESIMS found for C₂₀H₂₃FN₆O m/z 383.2 (M+1).

N-(6-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexanecarboxamide 969

Beige solid (79.0 mg, 0.189 mmol, 63.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.13-1.34 (3H, m), 1.39-1.51 (2H, m), 1.66 (1H, br d,J=11.25 Hz), 1.72-1.79 (2H, m), 1.82 (2H, brd, J=12.90 Hz), 1.94-2.11(6H, m), 2.22 (3H, s), 2.52-2.60 (1H, m), 2.87 (2H, br d, J=11.25 Hz),4.10-4.20 (1H, m), 7.77 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51Hz), 8.05 (1H, s), 8.10 (1H, s), 8.43 (1H, s), 8.47 (1H, s), 9.01 (1H,s), 10.37 (1H, s) ESIMS found for C₂₅H₃₁N₅O m/z 418.25 (M+1).

N-(6-(Isothiazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide970

Beige solid (28.0 mg, 0.079 mmol, 17.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.74 (2H, m), 1.75-1.84 (2H, m), 1.88 (2H, td,J=11.46, 2.06 Hz), 2.17 (3H, s), 2.51-2.57 (1H, m), 2.81 (2H, br d,J=11.53 Hz), 7.95 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.51 Hz),8.35 (1H, s), 8.54 (1H, s), 9.12 (1H, s), 9.25 (1H, s), 9.59 (1H, s),10.49 (1H, s); ESIMS found for C₁₉H₂₀N₄OS m/z 352.9 (M+1).

1-Isobutyl-N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide972

White solid (165.0 mg, 0.418 mmol, 49.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.72 (2H, m), 1.73-1.81(3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m),2.81-2.90 (2H, m), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51Hz), 8.04 (1H, s), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44 (1H, s),9.02 (1H, s), 10.45 (1H, s); ESIMS found for C₂₃H₂₆[²H₃]N₅O m/z 395.2(M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide 974

Beige solid (34.0 mg, 0.122 mmol, 25.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.78-0.91 (4H, m), 2.04-2.12 (1H, m), 7.86 (1H, dd,J=8.51, 1.65 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.78 Hz), 8.17 (1H, s),8.50 (1H, s), 8.57 (1H, s), 9.14 (1H, s), 10.93 (1H, s); ESIMS found forC₁₆H₁₃N₃O₂ m/z 280.1 (M+1).

(R)—N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 974

Light yellow solid (120.0 mg, 0.388 mmol, 41.0% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.83-1.97 (2H, m), 1.98-2.08 (1H, m), 2.20-2.31 (1H, m),3.82-3.91 (1H, m), 3.97-4.06 (1H, m), 4.54 (1H, dd, J=8.37, 5.63 Hz),7.90 (1H, dd, J=8.64, 1.51 Hz), 7.96 (1H, s), 8.16 (1H, d, J=8.51 Hz),8.25 (1H, s), 8.52 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 9.88 (1H, s);ESIMS found for C₁₇H₁₅N₃O₃ m/z 310.1 (M+1).

(R)—N-(6-(Oxazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide 975

Beige solid (19.0 mg, 0.059 mmol, 24.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.36-1.47 (1H, m), 1.56-1.64 (1H, m), 1.64-1.72 (1H, m),1.87 (1H, dt, J=8.58, 4.08 Hz), 2.52-2.59 (1H, m), 2.59-2.67 (1H, m),2.75 (1H, br dd, J=11.94, 8.92 Hz), 2.78-2.85 (1H, m), 2.99 (1H, br dd,J=12.08, 3.02 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.95 (1H, s), 8.13(1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s), 8.58 (1H, s), 9.12 (1H,s), 10.85 (1H, s); ESIMS found for C₁₈H₁₈N₄O₂ m/z 323.0 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 976

Beige solid (17.5 mg, 0.054 mmol, 24.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.78 (4H, m), 2.78-2.87 (1H, m), 3.33-3.40 (2H, m),3.88-3.96 (2H, m), 7.87 (1H, dd, J=8.64, 1.51 Hz), 7.95 (1H, s), 8.13(1H, d, J=8.78 Hz), 8.20 (1H, s), 8.54 (1H, s), 8.58 (1H, s), 9.13 (1H,s), 10.60 (1H, s); ESIMS found for C₁₈H₁₇N₃O₃ m/z 323.9 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide977

White solid (33.4 mg, 0.077 mmol, 43.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.41-1.53 (1H, m), 1.55-1.66 (1H, m), 1.69 (4H, br s),1.84 (2H, br d, J=10.98 Hz), 2.48 (4H, br s), 2.56-2.66 (1H, m), 2.82(1H, ddt, J=11.25, 7.55, 3.91, 3.91 Hz), 3.01 (1H, brt, J=12.21 Hz),3.14-3.21 (1H, m), 3.33-3.37 (1H, m), 4.11 (1H, br d, J=13.45 Hz), 4.40(1H, br d, J=13.17 Hz), 7.87 (1H, dd, J=8.51, 1.10 Hz), 7.95 (1H, s),8.13 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.53 (1H, s), 8.57 (1H, s), 9.14(1H, s), 10.64 (1H, s); ESIMS found for C₂₄H₂₇N₅O₃ m/z 434.0 (M+1).

1′-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide978

Beige solid (90.0 mg, 0.215 mmol, 61.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (2H, qd, J=11.85, 3.43 Hz), 1.58-1.71 (4H, m),1.75-1.86 (4H, m), 2.07-2.20 (3H, m), 2.12 (3H, s), 2.51-2.57 (1H, m),2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 7.86 (1H, dd,J=8.51, 1.65 Hz), 7.94 (1H, s), 8.12 (1H, d, J=8.78 Hz), 8.19 (1H, s),8.54 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.53 (1H, s); ESIMS found forC₂₄H₂₉N₅O₂ m/z 420.2 (M+1).

cis-4-Morpholino-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide979

Off-white solid (125.0 mg, 0.308 mmol, 51.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.15-1.27 (2H, m), 1.42-1.55 (2H, m), 1.91 (4H, br t,J=12.62 Hz), 2.17-2.26 (1H, m), 2.45-2.49 (4H, m), 2.51-2.53 (1H, m),3.52-3.59 (4H, m), 7.86 (1H, dd, J=8.51, 1.37 Hz), 7.95 (1H, s), 8.12(1H, d, J=8.51 Hz), 8.18 (1H, s), 8.52 (1H, s), 8.57 (1H, s), 9.12 (1H,s), 10.53 (1H, s); ESIMS found for C₂₃H₂₆N₄O₃ m/z 407.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide980

Beige solid (31.5 mg, 0.094 mmol, 49.2% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.54-1.69 (2H, m), 1.80-1.92 (2H, m), 1.98-2.06 (2H, m),2.23 (3H, s), 3.03-3.11 (1H, m), 3.13 (2H, s), 7.89 (1H, dd, J=8.51,1.65 Hz), 7.97 (1H, s), 8.16 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53 (1H,s), 8.58 (1H, s), 9.15 (1H, s), 10.01 (1H, s); ESIMS found forC₁₉H₂₀N₄O₂ m/z 337.1 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 981

Off-white solid (45.0 mg, 0.140 mmol, 42.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (4H, dt, J=6.79, 3.33 Hz), 2.62-2.70 (4H, m), 3.37(2H, s), 7.89 (1H, dd, J=8.78, 1.65 Hz), 7.96 (1H, s), 8.15 (1H, d,J=8.51 Hz), 8.26 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.14 (1H, s),10.01 (1H, s); ESIMS found for C₁₈H₁₈N₄O₂ m/z 323.1 (M+1).

(R)-2-(2-Methylpyrrolidin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide 982

Beige solid (8.0 mg, 0.024 mmol, 23.8% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.09 (3H, d, J=6.04 Hz), 1.41 (1H, dddd, J=12.32, 10.39, 8.30,6.31 Hz), 1.67-1.84 (2H, m), 1.91-2.02 (1H, m), 2.40 (1H, q, J=8.78 Hz),2.57-2.66 (1H, m), 3.13 (1H, d, J=16.19 Hz), 3.13-3.20 (1H, m), 3.55(1H, d, J=16.19 Hz), 7.89 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s), 8.16(1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.14 (1H,s), 9.98 (1H, s); ESIMS found for C₁₉H₂₀N₄O₂ m/z 337.2 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide983

Pale yellow solid (43.0 mg, 0.122 mmol, 37.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 3.23 (2H,s), 7.89 (1H, dd, J=8.51, 1.65 Hz), 7.96 (1H, s), 8.15 (1H, d, J=8.78Hz), 8.26 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 10.01 (1H,s); ESIMS found for C₁₉H₂₁N₅O₂ m/z 352.2 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 984

Beige solid (30.0 mg, 0.082 mmol, 25.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.79 (4H, m), 2.77-2.87 (1H, m), 3.33-3.40 (2H, m),3.91 (2H, br d, J=2.47 Hz), 3.93 (3H, s), 4.64 (2H, d, J=5.21 Hz), 5.56(1H, t, J=5.35 Hz), 7.68 (1H, dd, J=8.51, 1.37 Hz), 7.81 (1H, s), 7.94(1H, s), 8.05 (1H, d, J=8.51 Hz), 8.48 (1H, s), 9.09 (1H, s), 10.54 (1H,s); ESIMS found for C₂₀H₂₂N₄O₃ m/z 367.0 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide985

Beige solid (26.0 mg, 0.069 mmol, 12.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 1.86 (2H, td,J=11.60, 2.06 Hz), 2.16 (3H, s), 2.46-2.55 (1H, m), 2.77-2.85 (2H, m),3.93 (3H, s), 4.63 (2H, d, J=5.21 Hz), 5.56 (1H, t, J=5.35 Hz), 7.67(1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 7.94 (1H, s), 8.05 (1H, d,J=8.51 Hz), 8.48 (1H, s), 9.08 (1H, s), 10.50 (1H, s); ESIMS found forC₂₁H₂₅N₅O₂ m/z 380.0 (M+1).

3,3-Difluoro-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide 986

White solid (33.0 mg, 0.086 mmol, 28.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.75-2.90 (5H, m), 3.07 (2H, br t, J=5.21 Hz), 3.95 (2H,s), 4.11 (2H, t, J=5.35 Hz), 7.30 (1H, s), 7.68 (1H, dd, J=8.51, 1.65Hz), 7.97 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.55 (1H, s), 9.11 (1H, s),10.78 (1H, s); ESIMS found for C₂₀H₁₉F₂N₅O m/z 384.15 (M+1).

(R)—N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide 987

Beige solid (20.0 mg, 0.055 mmol, 34.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.67 (2H, quin, J=6.72 Hz), 1.78-1.90 (1H, m), 2.05-2.16(1H, m), 2.87 (1H, dt, J=10.15, 6.45 Hz), 2.97 (1H, dt, J=10.15, 6.72Hz), 3.07 (2H, t, J=5.49 Hz), 3.81 (1H, dd, J=9.06, 5.49 Hz), 3.95 (2H,s), 4.12 (2H, t, J=5.35 Hz), 7.30 (1H, s), 7.67 (1H, dd, J=8.51, 1.65Hz), 7.98 (1H, s), 8.07 (1H, d, J=8.78 Hz), 8.52 (1H, s), 9.09 (1H, s),10.38 (1H, s); ESIMS found for C₂₀H₂₂N₆O m/z 363.2 (M+1).

(R)—N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-3-carboxamide 988

Dark brown gum (36.0 mg, 0.096 mmol, 55.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31-1.56 (2H, m), 1.57-1.74 (2H, m), 2.32-2.46 (1H, m),2.52-2.66 (2H, m), 2.70-2.88 (2H, m), 3.07 (2H, t, J=5.35 Hz), 3.95 (2H,s), 4.11 (2H, t, J=5.21 Hz), 7.29 (1H, s), 7.65 (1H, dd, J=8.51, 1.65Hz), 7.93 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.08 (1H, s),10.79 (1H, s); ESIMS found for C₂₁H₂₄N₆O m/z 377.0 (M+1).

1-Methyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide989

White solid (3.0 mg, 0.008 mmol, 6.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.61-1.72 (2H, m), 1.73-1.80 (2H, m), 1.87 (2H, td, J=11.60, 2.06Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.76-2.86 (3H, m), 3.07 (2H, brt,J=5.21 Hz), 3.95 (2H, s), 4.10 (2H, t, J=5.49 Hz), 7.28 (1H, s), 7.65(1H, dd, J=8.51, 1.65 Hz), 7.93 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.52(1H, s), 9.09 (1H, s), 10.51 (1H, s); ESIMS found for C₂₂H₂₆N₆O m/z391.2 (M+1).

N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide990

Tan solid (31.0 mg, 0.062 mmol, 49.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 0.73 (2H, br s), 0.93-0.98 (2H, m), 1.62-1.71 (2H, m), 1.77 (2H,br d, J=10.70 Hz), 1.91-1.99 (2H, m), 2.53-2.59 (1H, m), 2.96 (2H, br d,J=11.25 Hz), 3.08 (2H, brt, J=5.21 Hz), 3.95 (2H, s), 4.11 (2H, br t,J=5.21 Hz), 7.29 (1H, s), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s),8.05 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.09 (1H, s), 10.51 (1H, s);ESIMS found for C₂₆H₂₉F₃N₆O m/z 499.2 (M+1).

1-Benzoyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide991

White solid (27.7 mg, 0.058 mmol, 70.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63 (2H, br s), 1.75-1.98 (2H, m), 2.69-2.96 (1H, m),2.86 (2H, ddt, J=11.22, 7.51, 3.81, 3.81 Hz), 3.02-3.17 (1H, m), 3.07(2H, brt, J=5.08 Hz), 3.95 (2H, s), 4.11 (2H, t, J=5.21 Hz), 7.29 (1H,s), 7.36-7.43 (2H, m), 7.43-7.50 (3H, m), 7.66 (1H, dd, J=8.51, 1.65Hz), 7.94 (1H, s), 8.06 (1H, d, J=8.78 Hz), 8.52 (1H, s), 9.10 (1H, s),10.61 (1H, s); ESIMS found for C₂₈H₂₈N₆O₂ m/z 481.2 (M+1).

tert-Butyl 6-((6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate 992

White solid (200.0 mg, 0.367 mmol, 78.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.37 (11H, s), 1.45-1.54 (4H, m), 2.37 (4H, s), 2.38 (4H,s), 3.21-3.30 (1H, m), 3.65 (2H, s), 3.81 (2H, br s), 3.88 (2H, br s),3.91 (3H, s), 7.69 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H, s), 8.02 (1H, d,J=8.78 Hz), 8.05 (1H, s), 8.47 (1H, s), 9.06 (1H, s), 10.44 (1H, s);ESIMS found for C₃₁H₄₀N₆O₃ m/z 545.3 (M+1).

N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide993

Beige solid (25.0 mg, 0.071 mmol, 21.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (4H, dt, J=6.79, 3.33 Hz), 2.62-2.69 (4H, m), 2.72(3H, s), 3.36 (2H, s), 7.82 (1H, dd, J=8.51, 1.92 Hz), 8.10 (1H, d,J=8.51 Hz), 8.15 (1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s), 9.11(1H, s), 9.99 (1H, s); ESIMS found for C₁₉H₂₀N₄OS m/z 353.1 (M+1).

N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide 994

Beige solid (44.0 mg, 0.119 mmol, 41.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.61 (4H, m), 2.72 (3H, s), 3.25 (2H, s), 3.60-3.68(4H, m), 7.82 (1H, dd, J=8.64, 1.78 Hz), 8.10 (1H, d, J=8.51 Hz), 8.15(1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.08 (1H,s); ESIMS found for C₁₉H₂₀N₄O₂S m/z 369.1 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide 995

Brown solid (31.0 mg, 0.081 mmol, 31.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 2.72 (3H,s), 3.23 (2H, s), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51Hz), 8.15 (1H, s), 8.30 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.00 (1H,s); ESIMS found for C₂₀H₂₃N₅OS m/z 382.2 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide996

Beige solid (50.0 mg, 0.131 mmol, 43.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64-1.71 (1H, m), 1.87 (1H, dd, J=9.47, 1.78 Hz), 2.63(1H, d, J=9.88 Hz), 2.72 (3H, s), 2.95 (1H, dd, J=9.88, 1.65 Hz), 3.46(2H, d, J=4.39 Hz), 3.59 (1H, dd, J=7.68, 1.92 Hz), 3.63 (1H, s), 3.88(1H, d, J=7.68 Hz), 4.41 (1H, s), 7.82 (1H, dd, J=8.64, 1.78 Hz), 8.10(1H, d, J=8.51 Hz), 8.15 (1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s),9.12 (1H, s), 9.98 (1H, s); ESIMS found for C₂₀H₂₀N₄O₂S m/z 381.1 (M+1).

N-(6-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide997

Tan solid (33.6 mg, 0.067 mmol, 47.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 0.73 (2H, br s), 0.94-0.99 (2H, m), 1.62-1.72 (2H, m), 1.74-1.81(2H, m), 1.91-1.99 (2H, m), 2.53-2.58 (1H, m), 2.93-2.99 (2H, m), 3.16(2H, brt, J=5.21 Hz), 4.06 (2H, br t, J=5.35 Hz), 4.22 (2H, s), 7.63(1H, dd, J=8.51, 1.65 Hz), 7.76 (1H, s), 7.98 (1H, s), 8.01 (1H, d,J=8.51 Hz), 8.47 (1H, s), 9.04 (1H, s), 10.46 (1H, s); ESIMS found forC₂₆H₂₉F₃N₆O m/z 499.25 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide998

Off-white solid (15.0 mg, 0.028 mmol, 41.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.73 (2H, br s), 0.94-0.99 (2H, m), 1.62-1.72 (2H, m),1.74-1.82 (2H, m), 1.91-1.99 (2H, m), 2.52-2.59 (1H, m), 2.93-3.03 (4H,m), 3.07 (2H, t, J=5.35 Hz), 4.08 (2H, s), 4.18 (2H, t, J=5.49 Hz), 4.66(2H, dt, J=47.85, 4.70 Hz), 7.64 (1H, dd, J=8.51, 1.37 Hz), 7.76 (1H,s), 8.00 (1H, s), 8.02 (1H, d, J=8.51 Hz), 8.48 (1H, s), 9.05 (1H, s),10.48 (1H, s); ESIMS found for C₂₈H₃₂F₄N₆O m/z 545.3 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 999

Yellow oil (5.6 mg, 0.013 mmol, 38.4% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.78 (4H, dt, J=6.72, 3.22 Hz), 2.66 (4H, br s), 2.98 (3H, dt,J=28.55, 4.95 Hz), 3.07 (2H, t, J=5.49 Hz), 3.36 (2H, s), 4.09 (2H, s),4.18 (2H, t, J=5.49 Hz), 4.66 (3H, dt, J=47.75, 4.95 Hz), 7.65 (1H, dd,J=8.51, 1.65 Hz), 7.82 (1H, s), 8.01 (1H, s), 8.05 (1H, d, J=8.51 Hz),8.47 (1H, s), 9.06 (1H, s), 9.96 (1H, s); ESIMS found for C₂₃H₂₇FN₆O m/z423.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide1000

Yellow solid (26.5 mg, 0.059 mmol, 52.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.35 (4H, br d, J=6.86 Hz), 1.69-1.79 (4H, m), 2.99 (2H,dt, J=28.90, 4.95 Hz), 3.08 (2H, br t, J=5.49 Hz), 3.19 (2H, s), 3.36(2H, br s), 4.09 (2H, s), 4.18 (2H, br t, J=5.49 Hz), 4.66 (2H, dt,J=47.85, 4.95 Hz), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.00(1H, s), 8.05 (1H, d, J=8.78 Hz), 8.48 (1H, s), 9.06 (1H, s), 10.08 (1H,s); ESIMS found for C₂₅H₂₉FN₆O m/z 449.25 (M+1).

cis-4-Methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 1001

White solid (33.4 mg, 0.087 mmol, 21.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.08-1.18 (2H, m), 1.45-1.55 (2H, m), 1.88-1.94 (2H, m),2.05-2.11 (2H, m), 2.52-2.58 (1H, m), 2.83 (3H, s), 3.09-3.16 (1H, m),3.25 (3H, s), 8.09 (1H, dd, J=8.65, 1.51 Hz), 8.19 (1H, d, J=8.51 Hz),8.44 (1H, s), 8.60 (1H, s), 9.21 (1H, s), 10.60 (1H, s); ESIMS found forC₂₀H₂₂N₄O₂S m/z 383.15 (M+1).

(R)—N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide 1002

Light yellow gum (31.1 mg, 0.065 mmol, 40.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.89 (6H, dd, J=11.11, 6.45 Hz), 1.50-1.58 (2H, m), 1.69(1H, br dd, J=8.37, 3.98 Hz), 1.78-1.86 (2H, m), 2.11 (1H, d, J=7.14Hz), 2.09-2.17 (1H, m), 2.28-2.37 (1H, m), 2.60-2.66 (1H, m), 2.75-2.84(2H, m), 2.98 (3H, dt, J=28.60, 4.95 Hz), 3.07 (2H, brt, J=5.49 Hz),4.07 (2H, s), 4.18 (2H, t, J=5.35 Hz), 4.66 (2H, dt, J=47.80, 4.95 Hz),7.64 (1H, dd, J=8.51, 1.65 Hz), 7.75 (1H, s), 8.00 (1H, s), 8.02 (1H, d,J=8.78 Hz), 8.46 (1H, s), 9.05 (1H, s), 10.69 (1H, s); ESIMS found forC₂₇H₃₅FN₆O m/z 479.3 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrimidin-2-ylmethyl)piperidine-4-carboxamide1003

Beige solid (75.0 mg, 0.175 mmol, 29.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.74 (2H, m), 1.74-1.82 (2H, m), 2.18 (2H, brt,J=10.70 Hz), 2.52-2.59 (1H, m), 2.98 (2H, br d, J=10.98 Hz), 3.74 (2H,s), 3.90 (3H, s), 7.41 (1H, t, J=4.80 Hz), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, d, J=0.82 Hz),8.34 (1H, s), 8.44 (1H, s), 8.79 (2H, d, J=4.94 Hz), 9.02 (1H, s), 10.44(1H, s); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrazin-2-ylmethyl)piperidine-4-carboxamide1004

Orange solid (20.0 mg, 0.047 mmol, 7.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.66-1.76 (2H, m), 1.76-1.83 (2H, m), 2.09 (2H, td,J=11.60, 2.33 Hz), 2.52-2.61 (1H, m), 2.90 (2H, br d, J=11.53 Hz), 3.67(2H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d,J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 8.54(1H, d, J=2.74 Hz), 8.58 (1H, dd, J=2.61, 1.51 Hz), 8.70 (1H, d, J=1.37Hz), 9.02 (1H, s), 10.46 (1H, s); ESIMS found for C₂₄H₂₅N₇O m/z 428.2(M+1).

1-((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1005

White solid (45.0 mg, 0.104 mmol, 17.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.74 (2H, m), 1.78-1.84 (2H, m), 2.18 (2H, td,J=11.53, 2.20 Hz), 2.35 (3H, s), 2.52-2.57 (1H, m), 2.89-2.96 (2H, m),3.87 (2H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d,J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02(1H, s), 10.45 (1H, s); ESIMS found for C₂₃H₂₅N₇O₂ m/z 432.2 (M+1).

1-(2-Hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1006

White solid (45.0 mg, 0.110 mmol, 18.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.09 (6H, s), 1.72 (4H, br d, J=2.74 Hz), 2.13 (2H, brs), 2.20 (2H, br s), 2.46-2.55 (1H, m), 2.99 (2H, br d, J=9.88 Hz), 3.90(3H, s), 4.04 (1H, br s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d,J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44(1H, s), 9.02 (1H, s), 10.44 (1H, s); ESIMS found for C₂₃H₂₉N₅O₂ m/z408.2 (M+1).

2-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide1008

White solid (35.0 mg, 0.108 mmol, 18.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.20 (6H, d, J=6.04 Hz), 3.75 (1H, spt, J=6.13 Hz), 3.91(3H, s), 4.15 (2H, s), 7.69 (1H, s), 7.73 (1H, dd, J=8.37, 1.78 Hz),8.17 (1H, br s), 8.18 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.57 (1H, s),9.20 (1H, s), 9.80 (1H, s); ESIMS found for C₁₈H₂₀N₄O₂ m/z 325.2 (M+1).

3-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)propanamide 1009

White solid (105.0 mg, 0.310 mmol, 43.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.08 (6H, d, J=6.04 Hz), 2.66 (2H, t, J=6.31 Hz), 3.58(1H, spt, J=6.08 Hz), 3.69 (2H, t, J=6.17 Hz), 3.84 (3H, s), 7.34 (1H,s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.87 (1H, s), 8.03 (1H, d, J=0.82Hz), 8.09 (1H, d, J=8.51 Hz), 8.55 (1H, s), 9.13 (1H, s), 10.55 (1H, s);ESIMS found for C₁₉H₂₂N₄O₂ m/z 339.2 (M+1).

tert-Butyl 2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) piperidin-1-yl)acetate 1010

White solid (75.0 mg, 0.167 mmol, 18.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.42 (9H, s), 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 2.22(2H, td, J=11.53, 2.20 Hz), 2.51-2.57 (1H, m), 2.83-2.91 (2H, m), 3.10(2H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d,J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02(1H, s), 10.46 (1H, s); ESIMS found for C₂₅H₃₁N₅O₃ m/z 450.2 (M+1).

2-(4-((6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)aceticacid 1011

White solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.76-1.90 (4H, m),2.41-2.48 (2H, m), 2.57-2.66 (1H, m), 3.10-3.19 (4H, m), 3.90 (3H, s),7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s),8.08 (1H, s), 8.36 (1H, br s), 8.44 (1H, s), 9.03 (1H, s), 10.53 (1H,s); ESIMS found for C₂₁H₂₃N₅O₃ m/z 394.2 (M+1).

2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 1012

Off-white solid (40.0 mg, 0.106 mmol, 48.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (2H, quin, J=5.97 Hz), 2.28 (3H, s), 2.56-2.64 (4H,m), 2.79-2.87 (4H, m), 3.36 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51,1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08-8.13 (2H, m), 8.36 (1H, s), 8.44(1H, s), 9.04 (1H, s), 9.96 (1H, s); ESIMS found for C₂₁H₂₆N₆O m/z 379.2(M+1).

N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide1013

Off-white solid (200.0 mg, 0.541 mmol, 99.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.75-1.85 (2H, m), 1.93-1.99 (2H, m), 2.79-2.90 (3H, m),3.28-3.34 (2H, m), 3.93 (3H, s), 7.98 (1H, s), 8.11 (1H, s), 8.26 (1H,s), 8.31 (1H, s), 8.47 (1H, s), 9.09 (1H, s), 10.71 (1H, s); ESIMS foundfor C₁₉H₂₀ClN₅O m/z 370.1 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide1014

Light brown solid (92.0 mg, 0.250 mmol, 50.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.46 (4H, br s), 2.60 (4H, br s), 3.23 (2H,s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H,s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.94 (1H, s); ESIMS foundfor C₂₀H₂₁[²H₃]N₆O m/z 368.2 (M+1).

N-(7-Fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide1015

Brown solid (20.0 mg, 0.054 mmol, 33.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (2H, br d, J=5.21 Hz), 1.58 (4H, quin, J=5.56 Hz),2.52 (4H, br s), 3.17 (2H, s), 7.92 (1H, d, J=11.53 Hz), 8.13 (1H, s),8.31 (1H, d, J=2.47 Hz), 8.33 (1H, d, J=7.68 Hz), 8.49 (1H, s), 9.05(1H, s), 9.93 (1H, s); ESIMS found for C₂₀H₁₉[²H₃]FN₅O m/z 371.2 (M+1).

N-(8-Fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide1016

Pale yellow solid (46.0 mg, 0.124 mmol, 40.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (2H, br d, J=4.94 Hz), 1.58 (4H, quin, J=5.56 Hz),2.51-2.57 (4H, m), 3.19 (2H, s), 7.62 (1H, dd, J=12.08, 1.10 Hz), 7.99(1H, s), 8.13 (1H, s), 8.40 (1H, d, J=0.82 Hz), 8.48 (1H, s), 9.16 (1H,s), 10.04 (1H, s); ESIMS found for C₂₀H₁₉[²H₃]FN₅O m/z 371.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 1018

Off-white solid (52.0 mg, 0.123 mmol, 51.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.91 (2H, qd, J=12.72, 3.02 Hz), 1.22-1.32 (1H, m), 1.44(2H, qd, J=12.72, 3.29 Hz), 1.79 (2H, br dd, J=13.17, 2.47 Hz),1.82-1.89 (2H, m), 2.29 (2H, d, J=6.59 Hz), 2.44-2.49 (1H, m), 2.53 (3H,s), 2.96-3.08 (2H, m), 3.49-3.59 (2H, m), 5.12 (1H, dq, J=58.00, 5.20Hz), 7.78 (1H, s), 7.79-7.83 (1H, m), 8.06-8.12 (2H, m), 8.50 (1H, s),9.10 (1H, s), 10.48 (1H, s); ESIMS found for C₂₄H₂₇FN₄O₂ m/z 423.2(M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 1019

Off-white solid (60.0 mg, 0.164 mmol, 49.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.53 (3H, s), 2.58 (4H, brs), 3.23 (2H, s), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12(1H, d, J=8.51 Hz), 8.16 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.00 (1H,s); ESIMS found for C₂₀H₂₃N₅O₂ m/z 366.2 (M+1).

1-Isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide1020

Off-white solid (40.0 mg, 0.102 mmol, 34.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.82(3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.59 (1H, m),2.64 (3H, s), 2.87 (2H, br d, J=11.25 Hz), 8.04 (1H, dd, J=8.51, 1.37Hz), 8.23 (1H, d, J=8.78 Hz), 8.47 (1H, s), 8.62 (1H, s), 9.24 (1H, s),10.64 (1H, s); ESIMS found for C₂₂H₂₇N₅O₂ m/z 394.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1021

White solid (66.0 mg, 0.147 mmol, 47.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.75-1.86 (1H, m), 1.91-2.01(2H, m), 2.05-2.22 (4H, m), 2.09 (2H, d, J=7.41 Hz), 2.78 (2H, br d,J=7.68 Hz), 3.07 (2H, br t, J=5.21 Hz), 3.95 (2H, s), 4.12 (2H, t,J=5.21 Hz), 7.31 (1H, s), 7.72 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, s),8.11 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.15 (1H, s), 9.91 (1H, d, J=4.12Hz); ESIMS found for C₂₅H₃₁FN₆O m/z 451.25 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1022

White solid (14.0 mg, 0.033 mmol, 46.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.54 (2H, qd, J=12.12, 3.70 Hz), 1.70 (2H, br d, J=10.98Hz), 2.47 (2H, br s), 2.64 (1H, tt, J=11.46, 3.50 Hz), 2.93-3.04 (4H,m), 3.07 (2H, br t, J=5.49 Hz), 4.08 (2H, s), 4.18 (2H, t, J=5.35 Hz),4.66 (2H, dt, J=47.80, 4.70 Hz), 7.63 (1H, dd, J=8.51, 1.65 Hz), 7.75(1H, s), 8.00 (1H, s), 8.02 (1H, d, J=8.78 Hz), 8.48 (1H, s), 9.05 (1H,s), 10.42 (1H, s); ESIMS found for C₂₃H₂₇FN₆O m/z 423.2 (M+1).

4-Fluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide1023

White amorphous solid (48.8 mg, 0.098 mmol, 88.2% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dt, J=13.52, 6.83Hz), 1.95 (2H, brt, J=11.66 Hz), 2.06-2.22 (4H, m), 2.09 (2H, d, J=7.68Hz), 2.78 (2H, br d, J=7.96 Hz), 2.99 (2H, dt, J=28.60, 4.95 Hz), 3.08(2H, t, J=5.49 Hz), 4.09 (2H, s), 4.18 (2H, t, J=5.49 Hz), 4.66 (2H, dt,J=47.85, 4.95 Hz), 7.70 (1H, dd, J=8.51, 1.65 Hz), 7.84 (1H, s), 8.01(1H, s), 8.08 (1H, d, J=8.78 Hz), 8.45 (1H, s), 9.11 (1H, s), 9.86 (1H,d, J=4.39 Hz); ESIMS found for C₂₇H₃₄F₂N₆O m/z 497.3 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 1024

Orange solid (3.0 mg, 0.007 mmol, 4.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 2.99 (2H, dt,J=28.60, 4.95 Hz), 3.07 (2H, t, J=5.49 Hz), 3.22 (2H, s), 4.09 (2H, s),4.18 (2H, t, J=5.35 Hz), 4.66 (2H, dt, J=47.80, 4.95 Hz), 7.66 (1H, dd,J=8.51, 1.65 Hz), 7.82 (1H, s), 8.01 (1H, s), 8.05 (1H, d, J=8.51 Hz),8.47 (1H, s), 9.07 (1H, s), 9.94 (1H, s); ESIMS found for C₂₄H₃₀FN₇O m/z452.2 (M+1).

tert-Butyl (6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamate 1025

White solid (96.0 mg, 0.296 mmol, 28.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.51 (9H, s), 3.90 (3H, s), 7.71 (1H, dd, J=8.51, 1.65Hz), 7.97 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.10 (1H, s),8.33 (1H, s), 8.97 (1H, s), 9.78 (1H, s); ESIMS found for C₁₈H₂₀N₄O₂ m/z325.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)but-2-ynamide 1026

Yellow solid (3.7 mg, 0.013 mmol, 2.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.05 (3H, s), 3.90 (3H, s), 7.78 (1H, dd, J=8.78, 1.65 Hz), 8.01(1H, d, J=8.78 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.34 (2H, s), 9.03 (1H,s), 11.06 (1H, br s); ESIMS found for C₁₇H₁₄N₄O m/z 290.9 (M+1).

N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide1027

White solid (2.0 mg, 0.005 mmol, 1.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.61-1.72 (2H, m), 1.73-1.80 (2H, m), 1.83-1.90 (2H, m), 2.16 (3H,s), 2.45-2.49 (1H, m), 2.81 (2H, br d, J=11.25 Hz), 3.93 (3H, s), 7.97(1H, s), 8.09 (1H, s), 8.25 (1H, s), 8.30 (1H, s), 8.48 (1H, s), 9.08(1H, s), 10.56 (1H, s); ESIMS found for C₂₀H₂₂ClN₅O m/z 384.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide1028

Off-white solid (57.0 mg, 0.163 mmol, 32.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.43 (2H, br d, J=5.21 Hz), 1.58 (4H, quin, J=5.56 Hz),2.52 (4H, br s), 2.53 (3H, s), 3.18 (2H, s), 7.80 (1H, s), 7.83 (1H, dd,J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.78 Hz), 8.16 (1H, s), 8.50 (1H, s),9.12 (1H, s), 9.98 (1H, s); ESIMS found for C₂₀H₂₂N₄O₂ m/z 351.15 (M+1).

2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide1029

Beige solid (200.0 mg, 0.506 mmol, 56.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.80-1.88 (2H, m), 2.00-2.06 (2H, m), 2.48 (2H, br s),2.67 (2H, br d, J=10.98 Hz), 2.83 (3H, s), 3.20 (2H, s), 4.27 (2H, br d,J=1.92 Hz), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.20 (1H, d, J=8.78 Hz),8.51 (1H, s), 8.61 (1H, s), 9.24 (1H, s), 10.09 (1H, s); ESIMS found forC₂₀H₂₁N₅O₂S m/z 396.15 (M+1).

(R)-2-(2-Methylpyrrolidin-1-yl)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide1030

White solid (25.2 mg, 0.065 mmol, 36.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.09 (3H, d, J=6.04 Hz), 1.42 (1H, dddd, J=12.18, 10.26,8.30, 6.59 Hz), 1.67-1.85 (2H, m), 1.90-2.02 (1H, m), 2.41 (1H, q,J=8.51 Hz), 2.57-2.67 (1H, m), 3.08 (2H, br t, J=5.21 Hz), 3.13-3.20(2H, m), 3.54 (1H, d, J=16.19 Hz), 3.95 (2H, s), 4.12 (2H, t, J=5.21Hz), 7.30 (1H, s), 7.68 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, s), 8.08(1H, d, J=8.51 Hz), 8.51 (1H, s), 9.10 (1H, s), 9.93 (1H, s); ESIMSfound for C₂₂H₂₆N₆O m/z 391.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide1031

Light olive-colored gum (43.2 mg, 0.111 mmol, 46.4% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.54-1.71 (2H, m), 1.80-1.93 (2H, m), 1.96-2.07 (2H,m), 2.23 (3H, s), 3.12 (1H, br d, J=14.27 Hz), 3.06-3.09 (2H, m), 3.12(2H, s), 3.95 (2H, s), 4.12 (2H, t, J=5.21 Hz), 7.30 (1H, s), 7.68 (1H,dd, J=8.51, 1.65 Hz), 7.99 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.51 (1H,s), 9.11 (1H, s), 9.96 (1H, s); ESIMS found for C₂₂H₂₆N₆O m/z 391.2(M+1).

trans-4-((6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylic acid 1032

Beige solid (135.0 mg, 0.357 mmol, 70.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.29-1.40 (2H, m), 1.49 (2H, qd, J=12.76, 3.16 Hz),1.85-1.94 (2H, m), 1.97 (2H, br dd, J=13.45, 2.74 Hz), 2.22 (1H, tt,J=12.18, 3.60 Hz), 2.51-2.58 (1H, m), 3.90 (3H, s), 7.74 (1H, dd,J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.08 (1H, s),8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.43 (1H, s), 12.07 (1H, brs); ESIMS found for C₂₁H₂₂N₄O₃ m/z 379.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinopropanamide1034

White solid (12.0 mg, 0.033 mmol, 12.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.44 (4H, br s), 2.57-2.63 (2H, m), 2.63-2.70 (2H, m),3.59 (4H, t, J=4.67 Hz), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz),8.00 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.44(1H, s), 9.03 (1H, s), 10.74 (1H, s); ESIMS found for C₂₀H₂₃N₅O₂ m/z366.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide1035

White solid (18.0 mg, 0.075 mmol, 23.92% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.07-2.16 (2H, m), 2.22-2.32 (6H, m), 2.85-2.95 (1H, m),3.22-3.30 (1H, m), 3.59 (4H, t, J=4.39 Hz), 3.91 (3H, s), 7.74 (1H, dd,J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s),8.35 (1H, s), 8.47 (1H, s), 9.01 (1H, s), 10.41 (1H, s); ESIMS found forC₂₂H₂₅N₅O₂ m/z 392. (M+1).

N-(6-(2-(Methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide1040

Beige solid (80.0 mg, 0.218 mmol, 91.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.46-1.60 (2H, m), 1.66-1.74 (2H, m), 2.43-2.49 (2H, m),2.59-2.68 (1H, m), 2.89 (3H, d, J=4.94 Hz), 2.93-3.01 (2H, m), 7.69 (1H,s), 7.70-7.74 (1H, m), 7.78 (1H, s), 7.90-7.98 (2H, m), 8.40 (1H, s),8.99 (1H, s), 10.40 (1H, s); ESIMS found for C₁₉H₂₁N₅OS m/z 368.15(M+1).

1-Methyl-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide1041

Yellow solid (32.0 mg, 0.084 mmol, 77.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.72 (2H, m), 1.73-1.80 (2H, m), 1.86 (2H, td,J=11.60, 2.06 Hz), 2.16 (3H, s), 2.44-2.49 (1H, m), 2.77-2.85 (2H, m),2.89 (3H, d, J=4.94 Hz), 7.69 (1H, s), 7.72 (1H, dd, J=8.64, 1.78 Hz),7.77 (1H, s), 7.89-7.97 (2H, m), 8.40 (1H, s), 8.99 (1H, s), 10.45 (1H,s); ESIMS found for C₂₀H₂₃N₅OS m/z 382.2 (M+1).

N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide1047

Yellow solid (22.0 mg, 0.050 mmol, 26.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.21 (6H, t, J=7.14 Hz), 1.73-1.85 (2H, m), 1.86-1.99(2H, m), 2.52-2.58 (2H, m), 2.66-2.75 (2H, m), 3.24 (2H, s), 3.52 (4H,q, J=7.14 Hz), 4.66-4.83 (1H, m), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.79(1H, s), 7.86 (1H, s), 7.98 (1H, d, J=8.51 Hz), 8.40 (1H, s), 9.01 (1H,s), 9.97 (1H, s); ESIMS found for C₂₃H₂₈FN₅OS m/z 442.2 (M+1).

N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide1048

Beige solid (25.0 mg, 0.057 mmol, 30.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.21 (6H, t, J=7.00 Hz), 2.19 (3H, s), 2.40 (4H, br s),2.58 (4H, br s), 3.21 (2H, s), 3.52 (4H, q, J=7.14 Hz), 7.74 (1H, dd,J=8.64, 1.78 Hz), 7.79 (1H, s), 7.86 (1H, s), 7.98 (1H, d, J=8.51 Hz),8.39 (1H, s), 9.01 (1H, s), 9.92 (1H, s); ESIMS found for C₂₃H₃₀N₆OS m/z439.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(1,4-oxazepan-4-yl)acetamide 1049

Beige solid (74.0 mg, 0.193 mmol, 35.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.87 (2H, quin, J=5.83 Hz), 2.83 (3H, s), 2.83-2.86 (4H,m), 3.43 (2H, s), 3.66-3.70 (2H, m), 3.74 (2H, t, J=6.04 Hz), 8.12 (1H,dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, d, J=0.82 Hz),8.62 (1H, s), 9.23 (1H, s), 10.15 (1H, s); ESIMS found for C₁₉H₂₁N₅O₂Sm/z 384.15 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide-2,2-d₂1051

White solid (20.0 mg, 0.054 mmol, 32.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.61 (4H, m), 2.83 (3H, s), 3.62-3.69 (4H, m), 8.12(1H, dd, J=8.64, 1.78 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62(1H, s), 9.23 (1H, s), 10.18 (1H, d, J=3.02 Hz); ESIMS found forC₁₈H₁₇[²H₂]N₅O₅₂S m/z 372.1 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(morpholino-d₈)acetamide 1052

Off-white solid (22.0 mg, 0.058 mmol, 7.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.83 (3H, s), 3.26 (2H, s), 8.12 (1H, dd, J=8.51, 1.65Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s),10.17 (1H, s); ESIMS found for C₁₈H₁₁[²H₈]N₅O₂S m/z 378.2 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide1057

White solid (22.5 mg, 0.056 mmol, 22.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63 (3H, t, J=19.07 Hz), 1.67-1.74 (2H, m), 1.75-1.81(2H, m), 2.22 (2H, td, J=11.60, 2.06 Hz), 2.52-2.60 (1H, m), 2.71 (2H,t, J=14.13 Hz), 2.95 (2H, br d, J=11.53 Hz), 7.87 (1H, dd, J=8.51, 1.65Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.54 (1H, s),8.58 (1H, s), 9.13 (1H, s), 10.58 (1H, s); ESIMS found for C₂₁H₂₂F₂N₄O₂m/z 401.2 (M+1).

trans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide1061

Grey solid (15.0 mg, 0.038 mmol, 19.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.07-2.16 (2H, m), 2.22-2.32 (6H, m), 2.54 (3H, s), 2.90 (1H,quin, J=7.14 Hz), 3.23-3.30 (1H, m), 3.59 (4H, t, J=4.39 Hz), 7.79 (1H,s), 7.80-7.83 (1H, m), 8.07-8.13 (2H, m), 8.54 (1H, s), 9.10 (1H, s),10.50 (1H, s); ESIMS found for C₂₂H₂₄N₄O₃ m/z 393.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide 1067

Off-white solid (41.0 mg, 0.116 mmol, 40.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.53 (3H, s), 2.55-2.60 (4H, m), 3.25 (2H, s), 3.62-3.69(4H, m), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d,J=8.78 Hz), 8.16 (1H, s), 8.51 (1H, s), 9.12 (1H, s), 10.08 (1H, s);ESIMS found for C₁₉H₂₀N₄O₃ m/z 353.15 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinopropanamide 1068

Beige solid (21.0 mg, 0.057 mmol, 20.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.44 (4H, br s), 2.53 (3H, s), 2.57-2.64 (2H, m),2.64-2.71 (2H, m), 3.59 (4H, t, J=4.53 Hz), 7.79 (1H, s), 7.81 (1H, dd,J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.50 (1H, s),9.11 (1H, s), 10.82 (1H, s); ESIMS found for C₂₀H₂₂N₄O₃ m/z 367.15(M+1).

1-(2-Hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1070

White solid (26.0 mg, 0.064 mmol, 22.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.74-1.81(2H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.59 (1H, m),2.87 (2H, br d, J=11.53 Hz), 4.09 (1H, s), 4.14 (3H, s), 8.01 (1H, dd,J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.51 (1H, s),8.73 (1H, s), 9.11 (1H, s), 10.52 (1H, s); ESIMS found for C₂₂H₂₈N₆O₂m/z 409.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide1071

Beige solid (27.0 mg, 0.075 mmol, 53.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.72-1.81 (6H, m), 2.74-2.83 (6H, m), 3.90 (3H, s), 7.75(1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07(1H, d, J=0.82 Hz), 8.35 (1H, s), 8.41 (1H, s), 9.04 (1H, s), 9.59 (1H,s); ESIMS found for C₂₁H₂₃N₅O m/z 362.2 (M+1).

2-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide1077

Off-white solid (79.0 mg, 0.208 mmol, 41.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.48-1.57 (2H, m), 1.83-1.93 (2H, m), 2.32-2.41 (2H, m),2.73-2.82 (2H, m), 3.18-3.27 (1H, m), 3.20 (2H, s), 3.24 (3H, s), 3.90(3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.78 Hz), 8.10(2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.94 (1H, s); ESIMSfound for C₂₁H₂₅N₅O₂ m/z 380.2 (M+1).

2-(4-Hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide1078

Off-white solid (84.0 mg, 0.230 mmol, 46.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.49 (2H, dtd, J=12.66, 9.52, 9.52, 3.70 Hz), 1.73-1.82(2H, m), 2.28-2.35 (2H, m), 2.76-2.83 (2H, m), 3.19 (2H, s), 3.47-3.56(1H, m), 3.90 (3H, s), 4.60 (1H, d, J=4.12 Hz), 7.77 (1H, dd, J=8.51,1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H,s), 9.04 (1H, s), 9.93 (1H, s); ESIMS found for C₂₀H₂₃N₅O₂ m/z 366.2(M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide1079

Beige solid (12.0 mg, 0.030 mmol, 14.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (3H, d, J=2.20 Hz), 0.88 (3H, d, J=2.20 Hz),1.53-1.62 (1H, m), 1.64-1.82 (4H, m), 1.82-1.93 (2H, m), 2.13-2.25 (2H,m), 2.54-2.62 (3H, m), 2.66-2.74 (1H, m), 2.80-2.89 (1H, m), 3.90 (3H,s), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H,s), 8.07 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.42 (1H,s); ESIMS found for C₂₄H₃₁N₅O m/z 406.25 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide1080

White solid (11.0 mg, 0.030 mmol, 15.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.56-1.66 (1H, m), 1.71-1.82 (2H, m), 1.82-1.93 (3H, m),2.27 (3H, s), 2.45-2.58 (3H, m), 2.62-2.72 (1H, m), 2.81-2.90 (1H, m),3.90 (3H, s), 7.74 (1H, dd, J=8.37, 1.51 Hz), 7.99 (1H, d, J=8.51 Hz),8.03 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s),10.43 (1H, s); ESIMS found for C₂₁H₂₅N₅O m/z 364.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide1081

Beige solid (5.0 mg, 0.013 mmol, 7.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.13-1.22 (2H, m), 1.43-1.54 (2H, m), 1.84-1.96 (4H, m), 2.11-2.20(1H, m), 2.18 (6H, s), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, d,J=0.82 Hz), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s);ESIMS found for C₂₂H₂₇N₅O m/z 378.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 1082

Brown solid (3.0 mg, 0.008 mmol, 4.6% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 1.35-1.46 (2H, m), 1.60-1.72 (2H, m), 2.04-2.12 (4H,m), 2.37 (6H, s), 2.39-2.44 (1H, m), 2.44-2.53 (1H, m), 2.58 (3H, s),7.61 (1H, s), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, d, J=8.51 Hz),8.10 (1H, s), 8.48 (1H, s), 9.01 (1H, s); ESIMS found for C₂₂H₂₆N₄O₂ m/z379.2 (M+1).

3-(Hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide 1083

White solid (310.4 mg, 0.891 mmol, 96.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.97 (6H, s), 3.41 (2H, d, J=5.76 Hz), 3.90 (3H, s), 4.56(1H, t, J=5.49 Hz), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51Hz), 8.04 (1H, s), 8.09 (1H, d, J=0.82 Hz), 8.37 (1H, s), 8.40 (1H, s),9.05 (1H, s), 10.13 (1H, s); ESIMS found for C₂₀H₂₀N₄O₂ m/z 349.2 (M+1).

Methyl trans-4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylate 1084

Light yellow solid (350.0 mg, 0.892 mmol, 40.0% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 1.47-1.58 (2H, m), 1.64 (2H, qd, J=12.76, 2.88 Hz),2.04 (2H, br dd, J=13.31, 2.88 Hz), 2.09 (2H, br dd, J=13.31, 3.16 Hz),2.39 (1H, tt, J=12.08, 3.57 Hz), 2.51 (1H, tt, J=11.87, 3.36 Hz), 3.68(3H, s), 3.96 (3H, s), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.93-7.99 (2H,m), 8.00 (1H, s), 8.16 (1H, s), 8.40 (1H, s), 8.94 (1H, s); ESIMS foundfor C₂₂H₂₄N₄O₃ m/z 393.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide1085

Off-white solid (105.0 mg, 0.312 mmol, 81.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.53 (2H, qd, J=12.12, 3.98 Hz), 1.70 (2H, br dd,J=12.21, 1.78 Hz), 2.44-2.49 (2H, m), 2.64 (1H, tt, J=11.60, 3.64 Hz),2.94-3.01 (2H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00(1H, d, J=8.51 Hz), 8.03 (1H, d, J=1.37 Hz), 8.08 (1H, d, J=0.82 Hz),8.35 (1H, s), 8.44 (1H, s), 10.40 (1H, s); ESIMS found for C₁₉H₂₀[²H]N₅Om/z 337.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(methyl-d₃)propyl-1,1,2,3,3,3-d₆)piperidine-4-carboxamide1086

Beige solid (160.0 mg, 0.399 mmol, 67.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.73 (2H, m), 1.74-1.80 (2H, m), 1.86 (2H, td,J=11.66, 2.20 Hz), 2.51-2.58 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.90(3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04(1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.45(1H, s); ESIMS found for C₂₃H₂₀[²H₉]N₅O m/z 401.3 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide1087

White solid (75.0 mg, 0.191 mmol, 64.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.63-1.73 (2H, m), 1.74-1.80(3H, m), 1.83-1.90 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.57 (1H, m),2.86 (2H, br d, J=11.25 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, d, J=1.37 Hz), 8.08 (1H, s),8.35 (1H, s), 8.44 (1H, s), 10.45 (1H, s); ESIMS found for C₂₃H₂₈[²H]N₅Om/z 393.25 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide1088

Light brown amorphous solid (13.9 mg, 0.032 mmol, 30.2% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 2.04 (6H, s), 2.14 (3H, s), 2.31 (4H, br d,J=1.92 Hz), 2.36-2.46 (4H, m), 2.38 (2H, s), 3.90 (3H, s), 7.76 (1H, dd,J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.09 (1H, s),8.36 (1H, s), 8.39 (1H, s), 9.04 (1H, s), 10.13 (1H, s); ESIMS found forC₂₅H₃₀N₆O m/z 431.25 (M+1).

1-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(1-methylpiperidin-4-yl)urea1090

Beige solid (35.0 mg, 0.096 mmol, 87.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.35-1.49 (2H, m), 1.77-1.88 (2H, m), 1.98-2.09 (2H, m),2.17 (3H, s), 2.63 (2H, ddd, J=5.35, 3.43, 1.65 Hz), 3.54 (1H, br dd,J=4.12, 1.65 Hz), 3.90 (3H, s), 7.15-7.24 (1H, m), 7.65 (1H, dd, J=8.51,1.65 Hz), 7.93 (3H, d, J=8.51 Hz), 8.07 (1H, s), 8.34 (1H, s), 8.88-8.96(2H, m); ESIMS found for C₂₀H₂₄N₆O m/z 365.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide1091

Beige solid (80.0 mg, 0.174 mmol, 50.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.35-1.47 (2H, m), 1.57 (2H, qd, J=12.76, 2.88 Hz),1.69-1.75 (2H, m), 1.84-1.93 (2H, m), 2.18 (3H, s), 2.23 (2H, br s),2.30 (2H, br s), 2.51-2.60 (1H, m), 2.64 (1H, tt, J=11.73, 3.22 Hz),3.44 (2H, br s), 3.50 (2H, br s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H,s), 8.43 (1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found forC₂₆H₃₂N₆O₂ m/z 461.3 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-tetrazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide1092.N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(pyrrolidin-1-yl)acetamide

Off-white solid (18.0 mg, 0.046 mmol, 7.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.74-1.82(3H, m), 1.82-1.94 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.61 (1H, m),2.87 (2H, br d, J=11.53 Hz), 4.29 (3H, s), 7.92 (1H, dd, J=8.51, 1.65Hz), 8.26 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.67 (1H, s), 9.27 (1H, s),10.67 (1H, s); ESIMS found for C₂₁H₂₇N₇O m/z 394.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(pyrrolidin-1-yl)acetamide 1093

Beige solid (45.0 mg, 0.134 mmol, 44.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78 (4H, dt, J=6.59, 3.29 Hz), 2.63-2.69 (4H, m), 3.35(2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d,J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.92 (1H, s);ESIMS found for C₁₉H₂₀[²H]N₅O m/z 337.2 (M+1).

Example 13

The screening assay for Wnt activity is described as follows. Reportercell lines can be generated by stably transducing cancer cell lines(e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells)with a lentiviral construct that includes a Wnt-responsive promoterdriving expression of the firefly luciferase gene.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 10-point dose-response curves starting from 10 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%. ForSp5-Luc reporter gene assays, the cells were plated at 4,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for 36 to 48 hours at 37°C. and 5% CO₂. Following incubation, 15 μl of BriteLite Plusluminescence reagent (Perkin Elmer) was added to each well of the384-well assay plates. The plates were placed on an orbital shaker for 2min and then luminescence was quantified using the Envision (PerkinElmer) plate reader. Readings were normalized to DMSO only treatedcells, and normalized activities were utilized for EC₅₀ calculationsusing the dose-response log (inhibitor) vs. response-variable slope(four parameters) nonlinear regression feature available in GraphPadPrism 5.0 (or Dotmatics). For EC₅₀ of >10 μM, the percent inhibition at10 μM is provided.

Table 2 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 2 Compound EC₅₀ (μM) 1 0.650 3 1.700 4 0.983 6 1.111 10 0.277 140.354 16 >10     69 3.700 71 3.900 72 0.920 73 0.485 75 0.520 76 0.70577 0.610 78 1.000 81 0.735 82 4.950 83 2.900 84 1.900 85 1.200 86 4.00087 1.000 89 0.765 90 1.100 91 >10     92 1.600 96 >10     110 1.100 1110.743 112 3.200 113 >10     114 0.835 115 2.400 116 7.100 118 3.600 1191.060 120 2.205 121 3.500 188 >10     248 >10     262 1.700 263 1.300264 >10     265 1.243 266 2.441 267 1.379 268 2.072 269 3.624270 >10     271 1.715 272 3.753 273 1.511 274 3.720 275 1.917 276 5.183277 5.264 278 0.413 279 5.650 280 2.325 281 >10 (47.0%) 282 >10 (49.3%)283 2.486 284 1.874 285 3.405 286 3.143 287 7.330 288 1.197 289 2.647290 5.231 291 4.641 292 3.385 293 3.222 294 5.186 295 2.571 296 3.479297 4.811 298 3.229 299 1.529 300 1.117 301 0.467 302 3.646 303 9.831304 2.317 305 1.942 306 3.698 307 >10 (25.9%) 308 1.809 309 >10 (43.5%)310 1.462 311 0.578 312 >10 (23.8%) 313 0.577 314 0.859 315 1.588 3162.845 317 1.266 318 0.442 320 1.142 324 0.145 325 0.552 326 0.438 3270.258 328 0.804 329 1.173 330 0.449 331 2.988 332 0.662 333 0.384 3340.787 335 0.993 336 0.395 338 7.369 340 0.932 341 4.097 342 7.215 3433.587 344 5.468 345 2.123 346 4.358 347 9.442 348 >10 (36.9%) 349 0.712350 1.005 351 2.521 352 2.958 353 5.711 354 2.320 355 3.512 358 0.413359 0.669 360 0.690 362 0.951 363 2.359 364 >10 (24.1%) 365 0.381 3660.334 367 0.524 368 0.689 369 0.743 370 0.608 371 0.643 372 3.398 3762.206 433 0.191 441 1.214 443 0.397 448 0.289 452 0.787 468 0.363 4701.184 472 0.382 475 0.701 477 0.327 481 1.536 483 1.872 487 0.446 5003.232 513 6.428 517 >10 (35.8%) 521 1.805 523 0.683 527 >10 (23.5%) 5281.154 531 1.062 535 >10 (44.9%) 537 4.800 547 2.226 554 0.272 561 1.456579 0.899 643 0.129 699 0.541 700 0.771 704 >10 (10.2%) 707 0.472 7110.703 713 9.246 718 0.589 731 3.046 737 1.291 741 0.444 743 9.487 7581.253 760 3.970 767 3.225 773 6.549 784 5.885 785 2.837 791 0.212 7950.471 798 0.594 803 3.551 822 0.517 826 0.603 831 0.706 839 0.776851 >10 (6.4%)  883 >10 (43.2%) 885 4.475 888 1.038 900 1.013 921 0.779932 0.946 939 2.072 946 1.881 952 1.469 953 >10 (48.7%) 959 4.235 9601.658 962 >10 (45.0%) 963 1.199 964 1.449 965 3.175 966 1.592 967 4.423968 >10 (38.0%) 969 3.926 970 1.356 971 0.720 972 0.420 973 0.609 9743.742 975 0.423 976 2.965 977 0.875 978 2.223 979 4.093 980 >10 (40.5%)981 1.085 982 2.709 983 5.533 984 2.987 985 1.160 986 1.380 987 >10(10.7%) 988 >10 (11.1%) 989 4.320 990 2.865 991 1.705 992 3.209 9937.974 994 7.901 995 >10 (43.8%) 996 4.389 997 3.886 998 2.249 999 3.1001000 4.324 1001 0.593 1002 1.916 1003 1.315 1004 0.618 1005 1.396 10060.704 1007 1.130 1008 3.350 1009 1.108 1010 2.021 1011 >10 (25.0%) 10122.718 1013 >10 (42.9%) 1014 2.364 1015 3.734 1016 4.057 1017 0.621 10180.608 1019 3.799 1020 1.142 1021 >10 (16.5%) 1022 1.370 1023 >10 (38.2%)1024 3.510 1025 >10     1026 0.513 1027 0.875 1028 3.870 1029 3.3361030 >10 (44.8%) 1031 3.969 1032 >10 (27.4%) 1034 2.040 1035 1.374 10373.643 1040 1.211 1041 0.776 1047 >10 (32.6%) 1048 9.381 1049 2.544 10510.480 1052 2.285 1057 >10 (5.0%)  1061 1.614 1064 4.119 1067 >10 (48.7%)1068 3.718 1070 0.738 1071 >10 (43.2%) 1073 >10 (5.9%)  1074 >10 (19.7%)1075 2.542 1076 0.640 1077 5.189 1078 4.033 1079 1.429 1080 1.218 10812.734 1082 9.902 1083 8.209 1084 3.407 1085 2.195 1086 0.485 1087 0.5141088 7.403 1090 0.722 1091 2.949 1092 0.247 1093 1.781

Example 14

Representative compounds were screened using the assay procedure forDYRK1A kinase activity as described below.

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 μM to 0.00016 μM) and compound transfer was performedusing the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-wellblack-walled round bottom plates (Corning).

The DYRK1A kinase assay was run using the Ser/Thr 18 peptide Z-lyteassay kit according to manufacturer's instructions (Life Technologies—aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as a ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant DYRK1A kinase, ATP and Ser/Thr peptide 18 wereprepared in 1× Kinase buffer to final concentrations of 0.19 μg/mL, 30μM, and 4 μM respectively. The mixture was allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 served as controlreactions. Additionally, an 11-point dose-response curve ofStaurosporine (1 uM top) was run to serve as a positive compoundcontrol.

After incubation, Development Reagent A was diluted in DevelopmentBuffer then added to the reaction and allowed to further incubate forone hour at room temperature. The plate was read at Ex 400 Em 455 todetect the coumarin signal and Ex 400 Em 520 to measure the signal(EnVision Multilabel Plate Reader, PerkinElmer).

The Emission ratio (Em) was calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation was then calculated using the followingformula: [1−((Em ratio×F100%)−C100%)/((C0%−C100%)+(Emratio×(F100%−F0%)))]. Dose-response curves were generated and inhibitoryconcentration (IC₅₀) values were calculated using non-linear regressioncurve fit in the Dotmatics' Studies Software (Bishops Stortford, UK).

Table 3 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 3 Compound EC₅₀ (μM) 1 0.0040 3 0.0037 4 0.0018 6 0.0013 10 0.001314 0.0015 16 0.0039 69 0.0062 71 0.0136 72 0.0025 73 0.0017 75 0.0026 760.0023 77 0.0016 78 0.0047 81 0.0015 82 0.0009 83 0.0012 84 0.0013 850.0014 86 0.0025 87 0.0033 89 0.0027 90 0.0030 91 0.0105 92 0.0065 960.0071 110 0.0047 111 0.0039 112 0.0206 113 0.0241 114 0.0019 115 0.0034116 0.0043 118 0.0096 119 0.0029 120 0.0048 121 0.0034 188 0.0286 2480.0374 262 0.0015 263 0.0013 264 0.3476 265 0.0037 266 0.0174 267 0.0294268 0.0058 269 0.0050 270 0.9524 271 0.0021 272 0.0140 273 0.0107 2740.0059 275 0.0047 276 0.0051 277 0.0023 278 0.0032 279 0.0078 280 0.0108281 0.0081 282 0.0115 283 0.0070 284 0.0071 285 0.0442 286 0.0649 2875.1353 288 0.0273 289 0.0137 290 0.0058 291 0.0082 292 0.0078 293 0.0050294 0.0124 295 0.0028 296 0.0143 297 0.0237 298 0.0135 299 0.0067 3000.0082 301 0.0020 302 0.0077 303 0.0080 304 0.0027 305 0.0082 306 0.0072307 6.2229 308 0.0024 309 0.0343 310 0.0062 311 0.0019 312 0.0127 3130.0025 314 0.0221 315 0.0123 316 0.0042 317 0.0370 318 0.0588 320 0.0099324 0.0021 325 0.0021 326 0.0029 327 0.0017 328 0.0019 329 0.0027 3300.0016 331 0.0018 332 0.0035 333 0.0012 334 0.0016 335 0.0038 336 0.0029338 0.0062 340 0.0019 341 0.0056 342 0.0065 343 0.0099 344 0.0105 3450.0040 346 0.0099 347 0.0104 348 0.0775 349 0.0065 350 0.0062 351 0.0136352 0.0215 353 0.0086 354 0.0044 355 0.0064 358 0.0006 359 0.0030 3600.0019 362 0.1319 363 0.0503 364 0.8403 365 0.0027 366 0.0106 367 0.0111368 0.0079 369 0.0028 370 0.0031 371 0.0024 372 0.0106 376 0.0055 4330.0019 441 0.0091 443 0.0022 448 0.0012 452 0.0004 468 0.0049 470 0.0027472 0.0032 475 0.0032 477 0.0011 481 0.0043 483 0.0113 487 0.0077 5000.0106 513 0.0104 517 0.0096 521 0.0016 523 0.0029 527 0.0098 528 0.0008531 0.0009 535 0.0045 537 0.0089 547 0.0034 554 0.0014 561 0.0015 5790.0250 643 0.0018 699 0.0021 700 0.0022 704 0.0082 707 0.0009 711 0.0010713 0.0031 718 0.0013 731 0.0014 737 0.0010 741 0.0009 743 0.0013 7580.0243 760 0.0038 767 0.0043 773 0.0038 784 0.0108 785 0.0101 791 0.0022795 0.0024 798 0.0031 803 0.0126 822 0.0041 826 0.0039 831 0.0032 8390.0038 851 5.0052 883 0.0089 885 0.0346 888 0.0014 900 0.0029 921 0.0021932 0.0169 939 0.0139 946 0.0230 952 0.0072 953 0.0168 959 0.0154 9600.0171 962 0.0236 963 0.0267 964 0.0052 965 0.0106 966 0.0020 967 0.0019968 0.0314 969 0.0500 970 0.0023 971 0.0342 972 0.0030 973 0.0029 9740.0135 975 0.0120 976 0.0061 977 0.0032 978 0.0039 979 0.0100 980 0.0191981 0.0137 982 0.0192 983 0.0223 984 0.0055 985 0.0041 986 0.0110 9870.0428 988 0.0249 989 0.0162 990 0.0213 991 0.0033 992 0.0253 993 0.0147994 0.0129 995 0.0133 996 0.0134 997 0.1864 998 0.0062 999 0.0209 10000.0111 1001 0.0073 1002 0.0285 1003 0.0021 1004 0.0020 1005 0.0015 10060.0030 1007 0.0024 1008 0.0075 1009 0.0062 1010 0.0026 1011 0.0026 10120.0130 1013 0.0171 1014 0.0094 1015 0.0058 1016 0.0291 1017 0.0031 10180.0025 1019 0.0289 1020 0.0104 1021 0.0422 1022 0.0042 1023 0.0087 10240.0170 1025 0.0780 1026 0.0050 1027 0.0500 1028 0.0225 1029 0.0257 10300.1938 1031 0.0704 1032 0.0012 1034 0.0019 1035 0.0026 1037 0.0102 10400.0048 1041 0.0033 1047 0.4629 1048 0.5407 1049 0.0069 1051 0.0146 10520.0180 1057 0.0027 1061 0.0043 1064 0.0067 1067 0.0188 1068 0.0053 10700.0076 1071 0.0165 1073 1.5241 1074 0.0069 1075 0.0137 1076 0.0084 10770.0045 1078 0.0060 1079 0.0057 1080 0.0032 1081 0.0022 1082 0.0102 10830.0042 1084 0.0017 1085 0.0024 1086 0.0025 1087 0.0035 1088 0.0093 10900.0069 1091 0.0014 1092 0.0627 1093 0.0117

Example 15

Representative compounds were screened using the assay procedure forGSK3β kinase activity as described below.

Each compound is dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 μM to 0.0003 M) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-well black-walledround bottom plates (Corning).

The GSK3β kinase assay is run using the Ser/Thr 09 peptide Z-lyte assaykit according to manufacturer's instructions (Life Technologies—aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant GSK3β kinase, ATP and Ser/Thr peptide 09 areprepared in 1× Kinase buffer to final concentrations of 0.04 μg/mL, 46μM, and 4 μM respectively. The mixture is allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 serve as controlreactions.

After incubation, diluted Development Buffer is added to the reactionand allowed to further incubate for one hour at room temperature. Theplate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400Em 520 to measure the signal (EnVision Multilabel Plate Reader,PerkinElmer).

The Emission ratio (Em) is calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation is then calculated using the followingformula: [1−((Em ratio×F100%)−C100%)/((C0%−C100%)+(Emratio×(F100%−F0%)))].

Dose-response curves are generated and inhibitory concentration (IC₅₀)values are calculated using non-linear regression curve fit in theDotmatics' Studies Software (Bishops Stortford, UK).

Table 4 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 4 Compound EC₅₀ (μM) 1 0.008 3 0.038 4 0.080 6 0.065 10 0.051 140.059 16 0.024 69 0.013 71 0.062 72 0.064 73 0.049 75 0.064 76 0.031 770.024 78 0.063 81 0.030 82 0.022 83 0.034 84 0.020 85 0.029 86 0.048 870.032 89 0.064 90 0.042 91 0.838 92 0.361 96 0.350 110 0.034 111 0.040112 0.292 113 0.586 114 0.032 115 0.030 116 0.024 118 0.079 119 0.007120 0.138 121 0.053 188 0.265 248 0.266 262 0.024 263 0.018 264 >10 2650.007 266 0.038 267 0.039 268 0.017 269 1.022 270 5.310 271 0.003 2720.105 273 0.048 274 0.025 275 0.115 276 0.006 277 0.104 278 0.007 2790.014 280 0.185 281 0.071 282 0.134 283 0.062 284 0.037 285 0.149 2860.186 287 9.838 288 0.020 289 0.062 290 0.075 291 0.043 292 0.173 2930.059 294 0.041 295 0.020 296 0.080 297 0.155 298 0.125 299 0.044 3000.031 301 0.010 302 0.038 303 0.089 304 0.029 305 0.051 306 0.066 3075.256 308 0.107 309 0.120 310 0.105 311 0.020 312 0.031 313 0.039 3140.012 315 0.044 316 0.509 317 0.030 318 0.012 320 0.010 324 0.030 3250.003 326 0.019 327 0.066 328 0.016 329 0.029 330 0.015 331 0.055 3320.039 333 0.060 334 0.047 335 0.071 336 0.083 338 0.067 340 0.257 3410.089 342 0.137 343 0.071 344 0.175 345 0.026 346 0.084 347 0.165 3480.221 349 0.066 350 0.033 351 0.130 352 0.110 353 0.029 354 0.037 3550.228 358 0.080 359 0.082 360 0.047 362 1.102 363 0.035 364 3.122 3650.052 366 0.116 367 0.056 368 0.051 369 0.101 370 0.089 371 0.023 3720.079 376 0.710 433 0.001 441 0.005 443 0.013 448 0.011 452 0.007 4680.007 470 0.004 472 0.008 475 0.023 477 0.006 481 0.004 483 0.045 4870.007 500 0.023 513 0.043 517 0.470 521 0.234 523 0.042 527 0.415 5280.096 531 0.050 535 0.087 537 0.095 547 0.104 554 0.038 561 0.012 5790.048 643 0.049 699 0.024 700 0.049 704 1.831 707 0.046 711 0.067 7130.098 718 0.079 731 0.042 737 0.062 741 0.107 743 0.063 758 0.050 7600.133 767 0.157 773 0.219 784 0.133 785 0.044 791 0.005 795 0.033 7980.031 803 0.164 822 0.009 826 0.007 831 0.010 839 0.017 851 5.005 8830.076 885 0.046 888 0.008 900 0.011 921 0.005 932 0.014 939 0.013 9460.038 952 0.008 953 0.023 959 0.045 960 0.015 962 0.057 963 0.006 9640.102 965 0.079 966 0.032 967 0.046 968 0.061 969 7.613 970 0.478 9710.034 972 0.064 973 0.020 974 0.096 975 1.094 976 0.146 977 0.246 9780.220 979 0.791 980 0.389 981 0.141 982 0.265 983 0.303 984 0.236 9850.283 986 0.021 987 2.316 988 1.093 989 0.298 990 0.100 991 0.029 9920.014 993 0.087 994 0.110 995 0.177 996 0.141 997 0.033 998 0.102 9990.086 1000 0.270 1001 0.009 1002 0.425 1003 0.043 1004 0.037 1005 0.0321006 0.050 1007 0.083 1008 0.091 1009 0.015 1010 0.053 1011 0.030 10120.155 1013 1.429 1014 0.096 1015 0.101 1016 0.087 1017 0.076 1018 0.0541019 0.158 1020 0.013 1021 1.585 1022 0.124 1023 0.838 1024 0.150 10250.100 1026 0.508 1027 3.073 1028 0.104 1029 0.018 1030 0.390 1031 0.3801032 0.072 1034 0.027 1035 0.010 1037 1.923 1040 0.098 1041 0.058 10474.745 1048 5.812 1049 0.012 1051 0.009 1052 0.011 1057 0.097 1061 0.0081064 0.126 1067 0.067 1068 0.036 1070 0.016 1071 2.733 1073 >10 10740.278 1075 0.015 1076 0.011 1077 0.032 1078 0.070 1079 0.048 1080 0.0561081 0.082 1082 0.210 1083 0.914 1084 0.040 1085 0.083 1086 0.028 10870.037 1088 0.937 1090 0.288 1091 0.069 1092 0.132 1093 0.047

Example 16

Representative compounds were screened using the assay procedure for tauphosphorylation activity described below.

SH-SY5Y cells (human neuroblastoma) were cultured in DMEM/F-12 mediumsupplemented with 15% FBS, Non-essential Amino Acid andPenicillin/Streptomycin. Two days before treatment, cells were seededonto 96 well plates at 5×10⁴ cells/well.

The above synthesized compounds were screened using the cell assayprocedure to assess decrease Tau phosphorylation at Ser396 (pSer396)described below.

DMSO-resuspended compounds were dispensed to 8 wells as a serialtitration from 10 μM to 4.6 nM final in medium and cells were exposedovernight (16-18 h) in a humidified incubator at 36.6 c before harvest.Wells were visually checked for cell death or change in morphology andsupernatants were tested for cytotoxicity by measurement of lactatedehydrogenase release (LDH, CytoToxOne kit, Promega) if necessary. Ascontrols, commercially available DYRK1A inhibitors, Harmine and Indywhich were shown to have good DYRK1A inhibition in the kinase assay withno CDK1 activity (EC₅₀ 18 and 53 nM respectively, 6 μM for CDK1) butweak EC₅₀ in the Tau assay >10 μM.

Cells were lysed with RIPA buffer complemented with phosphatase andprotease inhibitors then lysates were spun down at 12,000 g for 10 minto remove any cellular debris. Lysates are then either directly testedfor pSer396 by ELISA (Life Technology, Kit KHB7031) or loaded on NuPageBis-Tris gels for western blot analysis. Colorimetric detection of ELISAsignal is performed by Cytation3 plate reader (Biotek) and thechemiluminescence signal for HRP-linked antibodies used in westernblotting is detected using a Carestream Image Station. The same pSer396antibody is used for detection of pTau in both assays.

Blot densitometry for pSer396 and β-actin were analyzed using ImageJ(NIH) and pSer396 Tau ELISA signal was used to plot, draw the curvefitting, and determine each compounds EC₅₀ in Prism (GraphPad).

Table 5 shows the activity of representative compounds as providedherein.

TABLE 5 Compound pSer396 Tau EC₅₀ (μM) 1 0.149 3 0.288 4 0.671 6 0.47510 0.227 14 0.408 16 >10 69 0.383 71 1.510 72 0.757 73 0.199 75 0.227 760.219 77 0.184 78 0.265 81 0.452 82 0.315 83 0.432 84 0.454 85 0.392 860.682 87 0.414 89 0.364 90 0.302 91 4.700 92 3.900 96 2.000 110 0.636111 0.597 112 1.750 113 3.800 114 0.286 115 0.311 116 0.870 118 1.200119 0.418 121 1.030 188 4.220 248 0.905 262 0.174 263 0.119 264 >10 2650.656 266 1.200 267 0.555 268 0.478 269 4.300 270 >10 271 0.124 2721.660 273 0.492 274 0.535 275 0.232 276 0.150 277 1.080 278 0.076 2790.498 280 0.677 281 0.518 282 0.973 283 0.411 284 0.359 285 1.580 2861.150 288 0.159 289 0.185 290 0.490 291 0.716 292 1.350 293 0.668 2940.905 295 0.430 296 0.978 297 1.420 298 1.390 299 0.573 300 0.222 3010.108 302 0.628 303 0.783 304 0.210 305 0.247 306 0.592 307 2.080 3080.361 309 1.220 310 0.628 311 0.163 312 0.762 313 0.330 314 0.128 3150.346 316 8.780 317 0.200 318 0.072 320 0.280 324 0.180 325 0.440 3260.574 327 0.411 328 0.231 329 0.524 330 0.246 331 0.311 332 0.249 3331.100 334 0.820 335 0.289 336 0.820 338 1.700 340 2.300 341 1.600 3423.600 343 2.400 344 3.500 345 0.774 346 1.800 347 4.400 348 2.000 3490.351 350 0.417 351 0.846 352 1.300 353 0.724 354 1.200 355 1.700 3580.353 359 0.521 360 0.659 363 0.406 364 >10 365 1.200 366 1.100 3670.258 368 0.660 369 0.970 370 0.256 371 0.581 372 1.100 376 7.900 4330.032 441 0.073 443 0.289 448 0.106 452 0.912 468 0.039 470 0.095 4720.200 475 1.800 477 0.188 481 0.662 483 0.611 487 0.161 500 0.388 5130.864 517 1.300 521 1.100 523 2.200 527 2.400 528 0.323 531 0.146 5356.200 537 0.451 547 0.379 554 0.095 561 0.395 579 0.062 643 0.049 6990.423 700 0.513 704 10.000 707 0.449 711 0.443 713 5.000 718 0.294 7310.450 737 0.865 741 0.528 743 0.432 758 0.384 760 1.200 767 1.000 7732.200 784 2.200 785 0.485 791 0.055 795 0.401 798 0.320 803 3.700 8220.247 826 0.568 831 0.189 839 0.254 851 0.350 883 1.100 885 0.878 8880.195 900 0.180 921 0.109 932 0.357 939 0.274 946 0.571 952 0.269 9530.398 959 0.443 960 0.233 962 0.447 963 0.252 964 0.576 965 1.000 9660.236 967 0.373 968 2.700 970 0.862 971 0.191 972 0.355 973 0.102 9742.000 975 4.600 976 0.536 977 0.426 978 0.274 979 0.569 980 2.100 9811.100 982 1.100 983 1.500 984 2.100 985 3.200 986 0.387 987 >10 988 >10989 >10 990 1.800 991 10.000 992 0.350 993 0.702 994 1.900 995 2.400 9963.100 997 1.300 998 0.638 999 0.659 1000 1.500 1001 3.300 1002 1.9001003 0.732 1004 0.667 1005 0.898 1006 0.296 1007 0.435 1008 0.643 10090.068 1010 0.622 1011 >10 1012 0.555 1013 4.200 1014 0.767 1015 0.5231016 0.631 1017 0.320 1018 0.280 1019 1.500 1020 0.049 1021 5.700 10229.600 1023 1.800 1024 1.200 1025 >10 1027 2.200 1028 0.536 1029 0.2391030 1.200 1031 0.969 1034 0.430 1035 0.129 1037 >10 1040 1.600 10411.300 1047 >10 1048 4.700 1049 0.319 1051 0.147 1052 0.254 1057 0.3421061 0.058 1064 0.109 1067 0.729 1068 0.689 1070 0.091 1071 6.900 10741.300 1075 0.709 1076 0.041 1077 0.425 1078 0.458 1079 0.190 1080 0.2511081 0.470 1082 1.100 1086 0.168 1087 0.160 1088 8.600 1090 0.969 10910.869 1092 0.131 1093 0.422

Example 17

Representative compounds were screened using the cell-based assayprocedure for secreted β-amyloid 40 (Aβ340) peptide in an APPoverexpressing cell line described below.

SH-SY5Y cells (human neuroblastoma) were cultured in 1:1 DMEM/F-12medium supplemented with 15% FBS, 1% non-essential amino acids, and 1%penicillin/streptomycin. HEK293T cells (human kidney) were cultured inDMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin.

SH-SY5Y cells were infected with lentivirus to overexpress amyloid (A4)beta precursor protein (APP), hereafter referred to as the SH-SY5Y-APPcells. Specifically, in a 10 cm dish, HEK293T cells were seeded at2.5×10⁵ cells/mL and transfected with APP (Myc-DDK-tagged)-Human amyloidbeta (A4) precursor protein (APP), transcript variant 3 pLenti-ORFexpression construct (custom modification of RC215147 to includebicistronic IRES-puromycin, OriGene). Culture medium was changed 18 hpost-transfection before a first batch of viral supernatant was thenharvested at 42 h post-transfection. Culture medium was replenished oncemore before a second batch of viral supernatant was harvested 66 hpost-transfection. The two batches of viral supernatant were combinedand spun at 1800 g, then filtered through a 0.45 μm PVDF filter.

SH-SY5Y cells were seeded onto 6-well plates at 5.0×10⁵ cells/well andincubated overnight at 37° C. Cells were then infected with viralsupernatant at concentrations ranging from 10%→100% viral supernatant(diluted in Opti-MEM as appropriate), with 10 μg/mL Polybrene added forpermeability (H9268, Sigma). 24 hours post-transfection, the entirevolume from each well was replaced with regular SH-SY5Y medium. 4 dayspost-transfection, APP-overexpressing SH-SY5Y cells were selected for byadding puromycin (A11138-03, Gibco) to each well at a finalconcentration of 2 μg/mL. Puromycin-resistant cell were then expanded,harvested and banked. APP-overexpression was controlled byimmunoblotting for total APP and Myc-DDK.

The cell assay procedure start 18 h prior to treatment, as SH-SY5Y-APPcells were seeded onto 96-well plates at 2.0×10⁴ cells/well. The entire200 μL volume of medium was removed from all wells, and replenished toreset any Aβ40 peptide that may have been secreted prior to treatment.DMSO-resuspended compounds were dispensed to eight wells as a serialdilution from 10 μM to 4.6 nM final concentration in medium. At thistime, designated wells were seeded with SH-SY5Y cells that were seededand treated with puromycin at 10 μg/mL. Cells were exposed overnight(16-18 hours) in a 37° C. incubator before supernatant was harvested.Wells were visually checked for cell death before 150 μL of supernatantwas harvested from each well into V-bottom 96-well plates (3894,Corning). The original plates with seeded cells were tested forcytotoxicity by measure of adenosine triphosphate (ATP) release byadding CellTiter-Glo® diluted 1:4 in distilled water (G7573, Promega)and transferring lysed cells to a completely black 96-well plate to beread with the Cytation3. Plates containing supernatant were spun down at1200 g for 10 minutes to remove any cellular debris. Supernatant wasthen diluted 1:2 with a diluent from V-PLEX Aβ340 Peptide (6E10) Kit anddirectly tested for secreted Aβ340 peptide (K150SKE, Meso ScaleDiscovery). The signal was used to plot, draw the curve fitting, anddetermine each compounds EC₅₀ in Prism (GraphPad).

Table 6 shows the activity of representative compounds as providedherein.

TABLE 6 Compound Aβ40 IC₅₀ (μM) 1 3.96 72 2.1 76 1.2 77 1.1 78 0.889 812.3 82 5.1 83 >10 84 4.4 85 1.3 111 0.272 115 0.956 248 >10 262 2.2 2635.3 269 >10 271 4.6

Example 18

Representative compounds were screened using the assay procedure toassess the effect on cell viability as described below.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 8-point dose-response curves from 10 μM to 0.0045 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%.

For the Cell Viability Assays, the cells were plated at 2,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for four days hours at 37°C. and 5% CO₂. Eight replicates of DMSO-treated cells served as controlsand cells treated with compound were performed in duplicate.

After incubation, 10 μL of CellTiter-Glo (Promega) was added to eachwell allowed to incubate for approximately 12 minutes. This reagent“results in cell lysis and generation of a luminescent signalproportional to the amount of ATP present. The amount of ATP is directlyproportional to the number of cells present in culture, in agreementwith previous reports. The CellTiter-Glo® Assay generates a “glow-type”luminescent signal, produced by the luciferase reaction (Promega.com)”.

After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation3, BioTek). Dose-response curves were generated and EC₅₀ concentrationvalues were calculated using non-linear regression curve fit in theGraphPad Prism (San Diego, Calif.) or Dotmatics' Studies Software(Bishops Stortford, UK). For EC₅₀ of >10 μM, the percent inhibition at10 μM is provided.

Table 7 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 7 Compound EC₅₀ (μM) 1 0.130 3 2.802 4 1.937 6 1.256 10 0.324 140.898 16 7.845 69 3.931 71 8.098 72 0.911 73 0.769 75 1.322 76 1.556 770.767 78 1.844 81 0.949 82 2.710 83 6.336 84 1.954 85 1.637 86 >10    87 3.156 89 0.738 90 1.174 91 9.592 92 0.983 96 >10     110 1.049 1110.526 112 6.425 113 >10     114 3.892 115 3.505 116 6.495 118 5.936 1190.525 120 2.486 121 4.307 188 >10     248 >10     262 1.391 263 1.287264 8.750 265 4.348 266 6.316 267 2.025 268 2.774 269  2.3303270 >10     271 2.962 272 5.869 273 1.184 274 4.051 275 1.275 276 >10(29.6%) 277 1.401 278 1.232 279 >10 (52.4%) 280 9.566 281 >10     2826.613 283 3.121 284 2.670 285 7.023 286 3.292 287 >10 (47.8%) 288 2.660289 7.755 290 3.783 291 >10 (24.4%) 292 2.821 293 2.857 294 4.154 2963.465 297 5.718 298 2.381 299 2.237 300 1.298 301 0.550 302 >10 (34.9%)303 7.804 304 1.338 305 1.651 306 3.199 307 >10     308 >10 (32.0%)309 >10 (9.6%)  310 5.347 311 0.751 312 >10     313 0.711 314 1.196 3151.251 316 2.340 317 6.336 318 0.940 320 1.784 324 0.266 325 0.526 3260.400 327 1.585 328 0.929 329 4.119 330 6.784 331 3.115 332 1.003 3330.641 334 7.370 335 1.120 336 0.510 338 9.332 340 2.232 341 >10 (33.9%)342 >10 (40.0%) 343 7.886 344 7.678 345 3.076 346 9.663 347 >10 (48.5%)348 >10 (22.4%) 349 0.704 350 1.081 351 6.882 352 8.599 353 8.225 3544.992 355 8.634 358 2.372 359 0.261 360 0.570 362 5.476 363 3.057 3645.601 365 0.522 366 0.910 367 8.240 368 0.651 369 0.864 370 1.246 3711.063 372 8.816 376 4.195 433 0.615 441 5.268 443 1.676 448 0.626 4521.453 468 2.507 470 4.187 472 5.093 475 1.063 477 0.719 481 1.368 4837.343 487 2.684 500 >10 (25.1%) 513 9.064 517 >10 (27.5%) 521 3.629 5230.447 527 >10 (43.6%) 528 1.415 531 0.989 535 >10 (42.0%) 537 8.303 5470.931 554 0.366 561 0.924 579 0.954 643 0.115 699 0.834 700 0.623704 >10 (18.1%) 707 0.947 711 0.706 713 6.976 718 0.483 731 1.103 7374.342 741 0.462 743 1.544 758 1.336 760 3.284 767 9.054 773 >10 (48.4%)784 >10 (39.7%) 785 2.860 791 0.137 795 0.806 798 0.613 803 4.533 8220.708 826 0.897 831 0.911 839 1.177 851 >10 (30.4%) 883 >10 (35.5%) 8857.720 888 2.471 900 3.883 921 1.624 932 5.449 939 >10 (31.6%) 946 >10(42.6%) 952 7.090 953 >10 (40.3%) 959 >10 (45.0%) 960 6.673 962 >10(30.9%) 963 >10 (49.2%) 964 3.828 965 8.630 966 0.259 967 0.459 968 >10(14.5%) 969 2.885 970 1.255 971 1.197 972 0.757 973 0.391 974 3.161 9750.334 976 3.878 977 0.615 978 1.577 979 2.223 980 5.743 981 0.546 9821.212 983 4.619 984 3.128 985 1.722 986 3.305 987 >10 (10.6%) 988 >10(18.0%) 989 >10 (36.4%) 990 3.547 991 3.957 992 5.599 993 6.585 994 >10(36.8%) 995 >10 (47.6%) 996 >10 (32.2%) 997 5.060 998 4.753 999 7.5141000 7.295 1001 0.677 1002 >10 (37.6%) 1003 0.804 1004 0.678 1005 1.1261006 0.584 1007 0.922 1008 >10 (37.2%) 1009 2.351 1010 3.965 1011 >10(25.0%) 1012 3.195 1013 5.498 1014 5.417 1015 6.419 1016 6.136 10170.659 1018 0.498 1019 9.381 1020 1.032 1021 >10 (11.6%) 1022 3.3371023 >10 (39.9%) 1024 6.773 1026 0.554 1027 0.488 1028 3.523 1029 >10(34.6%) 1030 >10 (19.3%) 1031 3.892 1032 >10 (34.7%) 1034 3.242 10352.463 1037 >10 (32.7%) 1040 2.684 1041 2.763 1047 >10 (41.7%) 1048 4.0571049 >10 (31.3%) 1051 >10 (22.5%) 1052 >10 (40.7%) 1057 4.505 1061 1.5951064 4.851 1067 >10 (43.1%) 1068 >10 (46.0%) 1070 8.388 1071 >10 (26.2%)1073 >10 (8.5%)  1074 >10 (25.0%) 1075 5.281 1076 1.576 1077 5.246 10784.407 1079 2.605 1080 1.380 1081 4.648 1082 7.100 1083 0.901 1084 3.6661085 1.240 1086 0.592 1087 0.746 1088 9.194 1090 0.994 1091 1.246 10922.984

Example 19

Representative compounds were screened using primary human fibroblasts(derived from IPF patients) treated with TGF-β1 to determine theirability to inhibit the fibrotic process.

Human Fibroblast Cell Culture:

Primary human fibroblasts derived from IPF patients (LL29 cells)[¹Xiaoqiu Liu, et. al., “Fibrotic Lung Fibroblasts Show BluntedInhibition by cAMP Due to Deficient cAMP Response Element-BindingProtein Phosphorylation”, Journal of Pharmacology and ExperimentalTherapeutics (2005), 315(2), 678-687; ²Watts, K. L., et. al., “RhoAsignaling modulates cyclin D1 expression in human lung fibroblasts;implications for idiopathic pulmonary fibrosis”, Respiratory Research(2006), 7(1), 88] were obtained from American Type Culture Collection(ATCC) and expanded in F12 medium supplemented with 15% Fetal BovineSerum and 1% Penicillin/Streptomycin.

Compound Screening:

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:2, 11-point dose-responsecurves from 10 μM to 0.94 nM) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottomassay plates (Greiner Bio-One) with appropriate DMSO backfill for afinal DMSO concentration of 0.1%. LL29 cells were plated at 1,500cells/well in 70 μL/well F12 medium supplemented with 1% Fetal BovineSerum. TGF-β1 (Peprotech; 20 ng/mL) was added to the plates to inducefibrosis (ref. 1 and 2 above). Wells treated with TGF-β1 and containingDMSO were used as positive control, and cells with only DMSO werenegative control. Cells were incubated at 37° C. and 5% CO₂ for 4 days.Following incubation for 4 days, SYTOX green nucleic acid stain (LifeTechnologies [Thermo Fisher Scientific]) was added to the wells at afinal concentration of 1 μM and incubated at room temperature for 30min. Cells were then fixed using 4% formaldehyde (Electron MicroscopySciences), washed 3 times with PBS followed by blocking andpermeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3%Triton X-100 (Sigma) in PBS. Cells were then stained with antibodyspecific to α-smooth muscle actin (αSMA; Abcam) (ref. 1 and 2 above) in3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) inPBS, and incubated overnight at 4° C. Cells were then washed 3 timeswith PBS, followed by incubation with Alexa Flor-647 conjugatedsecondary antibody (Life Technologies [Thermo Fisher Scientific]) andDAPI in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100(Sigma) in PBS at room temperature for 1 hour. Cells were then washed 3times with PBS and plates were sealed for imaging. αSMA staining wasimaged by excitation at 630 nm and emission at 665 nm and quantifiedusing the Compartmental Analysis program on the CellInsight CX5 (ThermoScientific). Dead or apoptotic cells were excluded from analysis basedon positive SYTOX green staining. % of total cells positive for αSMAwere counted in each well and normalized to the average of 11 wellstreated with TGF-β1 on the same plate using Dotmatics' Studies Software.The normalized averages (fold change over untreated) of 3 replicatewells for each compound concentration were used to create dose-responsescurves and EC₅₀ values were calculated using non-linear regression curvefit in the Dotmatics' Studies Software. For EC₅₀ of >10 μM, the percentinhibition at 10 μM is provided.

Table 8 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 8 Compound EC₅₀ (μM) 1 0.135 3 0.103 4 0.068 6 >10 (45.6%) 10 >10(39.6%) 14 0.035 16 1.266 69 0.394 71 >10 (33.4%) 72 0.096 73 0.169 750.148 76 0.087 77 0.146 78 0.108 81 0.104 82 0.156 83 0.067 84 0.148 850.097 86 >10 (14.6%) 87 0.081 89 0.137 90 0.096 91 >10 (17.3%) 92 >10(16.7%) 96 0.677 110 0.286 111 0.280 112 0.546 113 2.113 114 0.735 1150.605 116 0.830 118 0.821 119 1.410 120 2.133 121 1.083 188 >10 (12.4%)248 7.922 262 0.043 263 0.134 264 >10 (11.7%) 265 2.563 266 0.697 2670.590 268 0.073 269 0.396 270 >10 (11.4%) 271 0.064 272 2.543 273 0.515274 0.195 275 0.431 276 0.336 277 0.245 278 0.211 279 1.202 280 0.909281 0.486 282 1.937 283 0.782 284 2.338 285 1.473 286 >10 (16.4%) 2872.347 288 0.532 289 >10 (14.3%) 290 1.056 291 >10 (49.6%) 292 2.216 2937.768 294 >10 (41.3%) 295 4.465 296 1.964 297 0.447 298 1.340 299 1.208300 0.511 301 4.807 302 0.901 303 0.817 304 0.150 305 5.510 306 0.282307 7.150 308 >10 (27.6%) 309 0.014 310 0.294 311 0.076 312 >10 (36.5%)313 0.105 314 0.045 315 1.822 316 1.082 317 0.174 318 0.073 320 0.069324 0.068 325 1.304 326 >10 (47.2%) 327 0.058 328 >10 (34.5%) 329 0.212330 0.020 331 0.096 332 0.291 333 0.061 334 0.063 335 0.111 336 >10(38.4%) 338 0.643 340 0.413 341 2.372 342 0.948 343 0.446 344 >10(24.3%) 345 >10 (38.0%) 346 0.965 347 5.220 348 1.457 349 0.145 3500.100 351 >10 (38.8%) 352 1.322 353 >10 (31.7%) 354 0.346 355 6.191 3580.145 359 0.127 360 0.094 362 0.782 363 0.387 364 >10 (15.0%) 365 4.799366 0.173 367 0.211 368 0.272 369 0.295 370 0.379 371 0.394 372 0.504376 >10 (21.0%) 433 0.052 441 0.057 443 0.371 448 0.059 452 0.220 4700.387 472 0.243 475 0.140 477 0.077 481 1.021 483 0.315 487 0.367 5000.675 513 1.353 517 >10 (29.9%) 521 1.991 523 >10 (32.6%) 527 >10(37.3%) 528 0.103 531 0.153 535 >10 (17.7%) 537 0.599 547 0.160 5540.190 561 0.600 579 0.167 643 0.138 699 0.234 700 0.275 704 4.383 7074.242 711 0.540 713 >10 (37.6%) 718 0.168 737 0.080 741 0.175 743 0.447758 0.265 760 0.765 767 >10 (33.2%) 773 >10 (30.3%) 784 >10 (37.4%) 7851.174 791 0.067 795 0.227 803 >10 (27.8%) 822 0.212 826 0.149 831 0.244851 0.692 883 >10 (14.0%) 885 2.620 900 0.449 921 0.075 932 0.594 9391.137 946 0.970 952 0.741 960 0.957 963 1.187 964 >10 (19.7%) 965 1.369966 0.014 967 0.079 968 >10 (24.1%) 969 0.935 970 1.239 971 0.866 9720.754 973 0.134 974 >10 (49.6%) 975 0.138 976 1.174 977 0.136 978 0.722979 1.032 980 >10 (40.3%) 981 0.605 982 0.767 983 0.679 984 1.239985 >10 (38.0%) 986 0.158 987 >10 (42.0%) 988 >10 (46.5%) 989 4.418 9900.782 991 2.678 992 2.972 993 1.487 994 0.567 995 1.254 996 1.204 9970.567 998 0.260 999 0.779 1000 2.957 1001 0.065 1002 >10 (27.5%) 10030.049 1004 5.041 1005 0.072 1006 0.061 1007 0.942 1008 0.318 1009 >10(22.4%) 1010 0.103 1011 >10 (15.9%) 1012 >10 (10.2%) 1013 2.436 10140.695 1015 >10 (9.7%)  1016 2.132 1017 0.097 1018 0.088 1019 6.5291020 >10 (30.6%) 1021 4.494 1022 0.222 1023 4.671 1024 0.549 1025 >10(31.4%) 1026 2.255 1029 >10 (31.8%) 1030 2.806 1031 >10 (39.2%) 10710.712 1073 >10     1074 >10    

Example 20

Representative compounds were screened using the following assayprocedure to determine their ability to inhibit IL-6 and thereforedemonstrate their anti-inflammatory properties.

Human Peripheral Blood Mononuclear Cells:

Fresh Normal PB MNC (Catalog # PB001, AllCells, Alameda, Calif.) wereshipped overnight at 4° C. and resuspended in Roswell Park MemorialInstitute (RPMI) 1640 Medium, with GlutaMAX Supplement (Catalog#61870127, ThermoFisher Scientific, Waltham, Mass.) supplemented with 1%Penicillin-Streptomycin (Catalog#15140163, ThermoFisher Scientific,Waltham, Mass.) and 1% fetal bovine serum (FBS) (Catalog #16140089,ThermoFisher Scientific, Waltham, Mass.) assay media.

Compound Screening:

Fresh normal human peripheral blood mononuclear cells (huPBMCs) wereresuspended in 1% FBS-RPMI assay media with 1% Penicillin-Streptomycin1% to a cell concentration of 1×10e6 cells/mL. Each compound wasdissolved in DMSO (Catalog # D8418-100 ml, Sigma-Aldrich, St. Louis,Mo.) as a 10 mM stock and used to prepare compound source plates. Serialdilution (1:3, 10-point dose-response curves starting from 10 μM) andcompound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale,Calif.) into 384-well white Proxiplate-Plus assay plates (Catalog#6008289, PerkinElmer, Shelton, Conn.) with appropriate DMSO backfillfor a final DMSO concentration of 0.25%. huPBMCs were plated at 5000cells/well in the 384-well Proxiplate-Plus assay plates and incubated at37° C.-5% CO₂ for 2 hours. 50 ng/mL of Lipopolysaccharides fromEscherichia coli 0111:B4 (Catalog #L5293-2ML, Sigma-Aldrich, St. Louis,Mo.) was added after 2 hours and cells were incubated for another 22hours at 37° C.-5% CO₂. After 22 hour incubation, a mixture of anti-IL6XL665 and anti-IL-6 Cryptate diluted in reconstitution buffer (Catalog#62IL6PEC, Cisbio Inc., Bedford, Mass.) was added to each well.Following incubation for 3 hours at room temperature, HomogeneousTime-Resolved Fluorescence (HTRF) was measured using the Envision(Perkin Elmer, Shelton, Conn.) at 665 nm and 620 nM. The ratio offluorescence at 665 nm to 620 nm was used as a readout for IL-6quantification. All samples were processed in duplicate. Readings werenormalized to DMSO treated cells and normalized activities were utilizedfor EC₅₀ calculations. EC₅₀ was determined using software generated byDotmatics Limited (Windhill Bishops Stortford Herts, UK) using theLevenberg-Marquardt 4 parameter fitting procedure with finite differentgradients. For EC₅₀ of >10 μM, the percent inhibition at 10 μM isprovided.

Table 9 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 9 Compound EC₅₀ (μM) 1 0.338 3 0.792 4 1.131 6 1.286 10 0.399 140.643 16 2.166 69 2.157 71 6.733 72 1.127 73 0.963 75 0.806 76 1.127 770.958 78 2.941 81 0.395 82 1.186 83 2.152 84 2.463 85 1.148 86 1.772 872.939 89 1.136 90 1.083 91  >10 (40.0%) 92  >10 (33.0%) 96 >10 (5.8%)110 0.484 112 2.989 113 1.917 114 1.140 115 1.913 116 1.334 118 3.606119 1.198 120 2.291 121 3.653 188 9.975 248 9.730 262 1.092 263 0.451264 >10 (4.0%) 265 2.997 266 1.933 267 9.407 268 8.174 269 3.389 2709.975 271 3.084 272 3.095 273 0.842 274 3.223 275 1.142 276 2.920277 >10 (4.0%) 278 3.988 279  >10 14.2%) 280  >10 (11.6%) 281 >10 (0%)  282 >10 (2.4%) 283 5.452 284 1.182 285 2.273 286 1.227 287 9.578 2881.236 289 3.195 290 4.782 291 9.827 292 1.116 293 1.170 294 6.228295 >10 (5.9%) 296 1.575 297 1.170 298 5.533 299 4.528 300 2.739 3010.393 302 7.698 303 5.235 304 1.144 305 1.144 306 2.517 307 >10 (4.3%)308 9.229 309 >10 (4.5%) 310 1.167 311 0.396 312 >10 (3.9%) 313 1.009314 1.273 315 0.819 316 0.395 317 1.897 318 1.031 320 1.264 324 0.321325 0.357 326 0.380 327 0.947 328 0.398 329 1.158 330 1.157 331 0.882332 1.066 333 0.790 334 0.263 335 0.401 336 0.569 338 4.458 340 0.562341  >10 (46.1%) 342 4.167 343  >10 (47.4%) 344 9.133 345 4.167 3469.438 347 >10 (4.5%) 348  >10 (19.0%) 349 0.307 350 0.578 351 3.009 3525.026 353  >10 (39.9%) 354 7.000 355 9.133 358 0.613 359 1.026 360 1.167362 9.153 363 1.223 364 >10 (5.8%) 365 0.526 366 1.120 367 1.153 3681.186 369 1.128 370 3.708 371 1.209 372 3.656 376  >10 (11.8%) 433 0.411441 3.351 443 3.289 448 2.185 452 2.973 468 5.776 470 3.550 472 5.409475 2.562 477 2.994 481 1.143 483 9.616 487 3.299 500 >10 (4.0%) 513 >10 (14.5%) 517 9.068 521 3.248 523 0.201 527 9.975 528 1.785 531 0.698535 >10 (3.1%) 537 1.243 547 1.119 554 0.439 561 0.634 579 1.017 6430.129 699 0.410 700 0.380 704 >10 (4.8%) 707 0.446 711 1.080 713 3.633718 0.406 731 1.179 737 1.179 741 0.380 743 1.127 758 2.871 760 1.245767 3.817 773 3.481 784 >10 (3.7%) 785 9.147 791 0.350 795 1.218 7981.268 803 3.317 822 3.260 826 3.294 831 0.812 839 3.276 851 >10 (2.9%)883 >10 (9.1%) 885 >10 (7.0%) 888 3.944 900 9.862 921 >10 (9.9%) 932 >10(7.5%) 939 >10 (3.6%) 946  >10 (18.2%) 952  >10 (10.1%) 959 >10 (6.1%)960 >10 (8.2%) 962 >10 (9.6%) 963 >10 (8.2%) 964 >10 (6.8%) 965 3.263967 1.130 968 9.238 969 9.123 970 1.132 971 1.220 972 1.134 973 0.395974  >10 (45.9%) 975 0.425 977 0.404 978 3.364 979 4.303 980 3.680 9811.104 982 2.787 983 >10 (9.1%) 984 8.760 985 3.891 986  >10 (13.4%)987 >10 (6.5%) 988 >10 (8.8%) 989  >10 (12.5%) 990 >10 (0%)   991 3.236992 >10 (2.6%) 993 8.836 994  >10 (31.8%) 995 8.930 996  >10 (10.6%) 997 >10 (28.6%) 998 7.082 999  >10 (30.3%) 1000 8.724 1001  >10 (49.7%)1002 >10 (5.9%) 1003 1.146 1004 1.177 1005 2.890 1006 1.128 1007 1.2621008 7.591 1009 1.840 1010 1.170 1011  >10 (15.3%) 1012 3.122 1013 6.8241014 3.201 1015 3.119 1016 >10 (5.4%) 1017 0.655 1018 0.441 1019 8.9731020 1.181 1021 >10 (5.1%) 1022 3.288 1023  >10 (20.7%) 1024  >10(33.1%) 1025  >10 (13.6%) 1026 9.523 1027 >10 (0%)   1028 1.934 1029 >10(7.3%) 1030 >10 (7.7%) 1031 >10 (2.0%) 1032 3.323 1034 3.325 1035 1.0271037 7.521 1040 1.177 1041 0.941 1047 >10 (4.5%) 1048 >10 (4.3%) 1049 >10 (10.4%) 1057 3.202 1061 0.947 1064 3.505 1067 8.940 1068 3.404 10706.470 1071 >10 (8.8%) 1073 >10 (3.3%) 1074 >10 (5.6%) 1075 3.2661076 >10 (3.0%) 1077 3.167 1078 3.242 1079 1.214 1080 1.073 1081 1.0971082 2.929 1083 8.734 1084 0.752 1085 0.453 1086 0.394 1087 0.470 10885.978 1090 0.484

Example 21

Representative compounds were screened using the cell-based assayprocedure for secreted cytokines in a Lipopolysaccharide-stimulatedmouse glial cell line described below.

BV-2 cells (mouse microglial cells) were cultured in 1:1 DMEM mediumsupplemented with 10% FBS, and 1% penicillin/streptomycin.

Compound Screening:

BV-2 cells are plated at 35,000 cells/well in a volume of 100 ul for atleast 4 hours before compounds are added. DMSO-resuspended compoundswere first dispensed in a 96 well plate and serial diluted from 10 μM to4.6 nM final concentration in medium. Compounds were added to cellsovernight. Two hundred fifty ng per milliliter of lipopolysaccharide(Escherichia coli 055:B5, SIGMA) was added for 5 h. Supernatant isremoved and saved for further cytokine detection. The original plateswith seeded cells were tested for cytotoxicity by measure of adenosinetriphosphate (ATP) release by adding CellTiter-Glo® diluted 1:4 indistilled water (G7573, Promega) and transferring lysed cells to acompletely black 96-well plate to be read with the Cytation3.Supernatant was then diluted 1:2 with a diluent from V-PLEX cytokine Kitand directly tested for the secreted cytokines TNFα, IL-6 and KC-GROusing electrochemiluminescence (Meso Scale Discovery). The standardcurve for each cytokine was used to convert the electrochemiluminescentsignal into pg of protein per mL. The signal was used to plot, draw thecurve fitting, and determine each compounds EC₅₀ in Prism (GraphPad).

Table 10 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 10 Compound TNFα EC₅₀ (μM) IL-6 EC₅₀ (μM) KC/Gro EC₅₀ (μM) 730.023 0.080 ND 81 >10 0.030 ND 83 ND 0.006 ND 262 3.2 1.5 ND 278 >100.217 ND 324 0.033 0.020 ND 338 0.724 0.144 ND 468 2.1 0.023 ND 500 1.20.034 0.007 966 0.060 0.022 0.071 1006 0.024 0.011 0.027 1017 0.0290.024 0.022 1020 0.597 0.087 0.708 1064 0.030 0.006 0.014 1070 ND 0.014ND 1076 1.8 0.008 0.291 ND = Not Determined

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, of Formula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H, halide, unsubstituted —(C₁₋₃ haloalkyl), andunsubstituted —(C₁₋₃ alkyl); R³ is a 5-membered heteroaryl optionallysubstituted with 1-4 R⁴⁵; with the proviso that R³ is not

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷, —(C₁₋₄alkylene)N(R⁴⁶)(R⁴⁷), —N(R⁴⁸)(R⁴⁹), —CF(C₁₋₉ alkyl)₂, —(C₁₋₄alkylene)_(p)O(C₃₋₉ alkyl), and —(C₂₋₉ alkynyl) optionally substitutedwith one or more halides; wherein each alkyl of —CF(C₁₋₉ alkyl)₂ is,independently, optionally substituted with one or more halides; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein; with the proviso thatR⁶ is not unsubstituted —(CH₂)tetrahydropyranyl; each R³⁶ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R⁴⁴, —C(═O)(R⁵⁰), —(C₁₋₄ alkylene)C(═O)OR⁵¹,—(C₁₋₄ alkylene)aryl optionally substituted with one or more halides,—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides, and —SO₂(R⁵²); wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein; alternatively, two R³⁶ attached to the same carbon atom cantogether represent ═O to form a carbonyl group; each R³⁷ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —N(R⁵³)₂, —C(═O)(R⁵⁰), —C(═O)OR⁵¹, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁸independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴⁰ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴¹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴³ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴⁴ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴⁵ is independently selected from the group consisting of H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; alternatively, two adjacent R⁴⁵ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹; R⁴⁶ is attached to the nitrogenand is selected from the group consisting of H, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein;R⁴⁷ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; R⁴⁸ is attached to the nitrogenand selected from the group consisting of H, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),and unsubstituted —(C₁₋₅ haloalkyl); R⁴⁹ is attached to the nitrogen andis selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; R⁵⁰ isselected from the group consisting of H, unsubstituted —(C₃₋₅ alkyl),unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; R⁵¹ is selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionally substituted with one ormore halides or unsubstituted —(C₁₋₅ alkyl), —(C₁₋₄alkylene)_(p)heteroaryl optionally substituted with one or more halidesor unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with one or more halides or one or moreunsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; R⁵² is selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)aryl optionally substituted with one or more halides orunsubstituted —(C₁₋₅ alkyl), —(C₁₋₄ alkylene)_(p)heteroaryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl), and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein; each R⁵³ is independently selected from thegroup consisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), and unsubstituted —(C₂₋₅ alkynyl); each p is independently 0or 1; and with the proviso that Formula I is not a structure selectedfrom the group consisting of:


2. The compound of claim 1, wherein R¹, R², R⁴, and R⁵ are H.
 3. Thecompound of claim 2, wherein R³ is a pyrazolyl optionally substitutedwith 1-4 R⁴⁵.
 4. The compound of claim 2, wherein R³ is an unsubstitutedpyrazolyl.
 5. The compound of claim 3, wherein R³ is a pyrazolylsubstituted with one —(C₁₋₃ alkyl).
 6. The compound of claim 2, whereinR³ is an imidazolyl optionally substituted with 1-4 R⁴⁵.
 7. The compoundof claim 6, wherein R³ is a imidazolyl substituted with one —(C₁₋₃alkyl).
 8. The compound of claim 2, wherein R³ is a triazolyl optionallysubstituted with 1-4 R⁴⁵.
 9. The compound of claim 2, wherein R³ is anunsubstituted triazolyl.
 10. The compound of claim 8, wherein R³ is atriazolyl substituted with one —(C₁₋₃ alkyl).
 11. A compound, or apharmaceutically acceptable salt thereof, of Formula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H, halide, unsubstituted —(C₁₋₃ haloalkyl), andunsubstituted —(C₁₋₃ alkyl); R³ is selected from the group consistingof:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; wherein any one of thenitrogen atoms attached to R⁷, R¹¹, R¹⁵, R¹⁸, or R²¹ can serve as thepoint of attachment of R³ to the isoquinoline ring; wherein any one ofthe carbon atoms attached to R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹,R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, orR³⁵ can serve as the point of attachment of R³ to the isoquinoline ring;so that: when the nitrogen atom to which R⁷ is attached serves as thepoint of attachment of R³ to the isoquinoline ring, then R⁷ is a singlebond connecting R³ to the isoquinoline ring; when the carbon atom towhich R⁸ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R⁸ is a single bond connecting R³ to theisoquinoline ring; when the carbon atom to which R⁹ is attached servesas the point of attachment of R³ to the isoquinoline ring, then R⁹ is asingle bond connecting R³ to the isoquinoline ring; when the carbon atomto which R¹⁰ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁰ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹¹ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹¹ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹² is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹² is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R¹³ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹³ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁴ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁴ is a single bond connecting R³to the isoquinoline ring; when the nitrogen atom to which R¹⁵ isattached serves as the point of attachment of R³ to the isoquinolinering, then R¹⁵ is a single bond connecting R³ to the isoquinoline ring;when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring; when the carbon atom to whichR¹⁷ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁷ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹⁸ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹⁸ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁰ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁰ is a single bond connecting R³ to the isoquinoline ring; when thenitrogen atom to which R²¹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²¹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²² is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²² is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²³ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²³ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁴ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁴ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁵ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁵ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁶ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁶ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁷ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁷ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁸ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁸ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³⁰ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³⁰ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³¹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³¹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³² is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³² is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³³ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³³ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³⁴ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³⁴ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³⁵ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³⁵ is a single bond connecting R³to the isoquinoline ring; R⁶ is selected from the group consisting of—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶,—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁷,—(C₁₋₄ alkylene)N(R⁴⁶)(R⁴⁷), —N(R⁴⁸)(R⁴⁹), —CF(C₁₋₉ alkyl)₂, —(C₁₋₄alkylene)_(p)O(C₃₋₉ alkyl), and —(C₂₋₉ alkynyl) optionally substitutedwith one or more halides; wherein each alkyl of —CF(C₁₋₉ alkyl)₂ is,independently, optionally substituted with one or more halides; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein; with the proviso thatR⁶ is not unsubstituted —(CH₂)tetrahydropyranyl; R⁷ is selected from thegroup consisting of a single bond, H, unsubstituted —(C₁₋₉ alkyl),unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein; R⁸, R⁹, and R¹⁰ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein; alternatively, one of R⁷and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹; R¹¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; R¹², R¹³, and R¹⁴ areindependently selected from the group consisting of a single bond, H,halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; alternatively, one of R¹¹ and R¹², R¹² and R¹³,or R¹⁴ and R¹¹ are taken together to form a ring which is selected fromthe group consisting of -heterocyclyl optionally substituted with 1-10R⁴⁰ and -carbocyclyl optionally substituted with 1-12 R⁴¹; R¹⁵ isselected from the group consisting of a single bond, H, unsubstituted—(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)OR⁴², —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein; R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein; alternatively, one of R¹⁵and R¹⁶ or R¹⁶ and R¹⁷ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹; R¹⁸ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; R¹⁹ and R²⁰ are independentlyselected from the group consisting of a single bond, H, halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; alternatively, one of R¹⁸ and R¹⁹ or R¹⁸ andR²⁰ are taken together to form a heterocyclyl optionally substitutedwith 1-10 R⁴⁰; R²¹ is selected from the group consisting of a singlebond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; R²² and R²³ are independentlyselected from the group consisting of a single bond, H, halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; alternatively, R²² and R²³ are taken togetherto form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹; R²⁴, R²⁵, and R²⁶ areindependently selected from the group consisting of a single bond, H,halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; with the proviso that when R²⁵ is a single bondconnecting R³ to the isoquinoline ring, R²⁴ and R²⁶ are not methyls;alternatively, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹; R²⁷, R²⁸, and R²⁹ are independently selectedfrom the group consisting of a single bond, H, halide, unsubstituted—(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R³⁸, and -carbocyclyl optionally substituted with1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;alternatively, R²⁷ and R²⁸ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹; R³⁰ and R³¹ are independently selected from the groupconsisting of a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl),unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein; alternatively, R³⁰ and R³¹are taken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰ and-carbocyclyl optionally substituted with 1-12 R⁴¹; R³² and R³³ areindependently selected from the group consisting of a single bond, H,halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl),—N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; R³⁴ and R³⁵ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —N(R⁵³)₂, —(C₁₋₄ alkylene)_(p)OR⁴²,—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein; alternatively, R³⁴ and R³⁵are taken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰ and-carbocyclyl optionally substituted with 1-12 R⁴¹; each R³⁶ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —(C₁₋₄ alkylene)_(p)heterocyclyl optionallysubstituted with 1-10 R⁴³, —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R⁴⁴, —C(═O)(R⁵⁰), —(C₁₋₄ alkylene)C(═O)OR⁵¹,—(C₁₋₄ alkylene)aryl optionally substituted with one or more halides,—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides, and —SO₂(R⁵²); wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein; alternatively, two R³⁶ attached to the same carbon atom cantogether represent ═O to form a carbonyl group; each R³⁷ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)OR⁴², —N(R⁵³)₂, —C(═O)(R⁵⁰), —C(═O)OR⁵¹, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁸independently is selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴⁰ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴¹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴² is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴³ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴⁴ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;R⁴⁶ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; R⁴⁷ is attached to the nitrogenand is selected from the group consisting of unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein;R⁴⁸ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl); R⁴⁹is attached to the nitrogen and is selected from the group consisting of—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸,and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12R³⁹; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;R⁵⁰ is selected from the group consisting of H, unsubstituted —(C₃₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl),—(C₁₋₄ alkylene)_(p)heteroaryl optionally substituted with one or morehalides or unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; R⁵¹ is selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —(C₁₋₄ alkylene)_(p)aryl optionally substituted with one ormore halides or unsubstituted —(C₁₋₅ alkyl), —(C₁₋₄alkylene)_(p)heteroaryl optionally substituted with one or more halidesor unsubstituted —(C₁₋₅ alkyl), and —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with one or more halides or one or moreunsubstituted —(C₁₋₅ alkyl); wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; R⁵² is selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)aryl optionally substituted with one or more halides orunsubstituted —(C₁₋₅ alkyl), —(C₁₋₄ alkylene)_(p)heteroaryl optionallysubstituted with one or more halides or unsubstituted —(C₁₋₅ alkyl), and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₅ alkyl); wherein —(C₁₋₄alkylene) is, optionally substituted with one or more substituents asdefined anywhere herein; each R⁵³ is independently selected from thegroup consisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), and unsubstituted —(C₂₋₅ alkynyl); each X is O or S; and eachp is independently 0 or 1; and with the proviso that Formula I is not astructure selected from the group consisting of:


12. The compound of claim 11, wherein R¹, R², R⁴, and R⁵ are H.
 13. Thecompound of claim 12, wherein R³ is selected from the group consistingof:

and X is O or S.
 14. The compound of claim 13, wherein R³ is selectedfrom the group consisting of:


15. The compound of claim 14, wherein R³ is selected from the groupconsisting of:

wherein R⁷, R¹¹, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁸, R²⁹, and R³² are independentlyselected from the group consisting of H and —(C₁₋₃ alkyl).
 16. Thecompound of claim 1, wherein R⁶ is a —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁶.
 17. The compound of claim 5,wherein R⁶ is a —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁶.
 18. The compound of claim 11, wherein R⁶ is a —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁶.
 19. Thecompound of claim 15, wherein R⁶ is a —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁶.
 20. The compound of claim 16,wherein R⁶ is a -heterocyclyl optionally substituted with 1-2 R³⁶. 21.The compound of claim 17, wherein R⁶ is a -heterocyclyl optionallysubstituted with 1-2 R³⁶.
 22. The compound of claim 18, wherein R⁶ is a-heterocyclyl optionally substituted with 1-2 R³⁶.
 23. The compound ofclaim 19, wherein R⁶ is a -heterocyclyl optionally substituted with 1-2R³⁶.
 24. The compound of claim 16, wherein R⁶ is a —CH₂heterocyclyloptionally substituted with 1-2 R³⁶.
 25. The compound of claim 17,wherein R⁶ is a —CH₂heterocyclyl optionally substituted with 1-2 R³⁶.26. The compound of claim 18, wherein R⁶ is a —CH₂heterocyclyloptionally substituted with 1-2 R³⁶.
 27. The compound of claim 19,wherein R⁶ is a —CH₂heterocyclyl optionally substituted with 1-2 R³⁶.28. The compound of claim 20, wherein R⁶ is either a piperidinyl or apyrrolidinyl both optionally substituted with 1-2 R³⁶.
 29. The compoundof claim 21, wherein R⁶ is either a piperidinyl or a pyrrolidinyl bothoptionally substituted with 1-2 R³⁶.
 30. The compound of claim 22,wherein R⁶ is either a piperidinyl or a pyrrolidinyl both optionallysubstituted with 1-2 R³⁶.
 31. The compound of claim 23, wherein R⁶ iseither a piperidinyl or a pyrrolidinyl both optionally substituted with1-2 R³⁶.
 32. The compound of claim 28, wherein R⁶ is a piperidinylsubstituted with one —(C₁₋₅ alkyl).
 33. The compound of claim 29,wherein R⁶ is a piperidinyl substituted with one —(C₁₋₅ alkyl).
 34. Thecompound of claim 30, wherein R⁶ is a piperidinyl substituted with one—(C₁₋₅ alkyl).
 35. The compound of claim 31, wherein R⁶ is a piperidinylsubstituted with one —(C₁₋₅ alkyl).
 36. The compound of claim 28,wherein R⁶ is a piperidinyl substituted with one —(C₁₋₃ haloalkyl). 37.The compound of claim 29, wherein R⁶ is a piperidinyl substituted withone —(C₁₋₃ haloalkyl).
 38. The compound of claim 30, wherein R⁶ is apiperidinyl substituted with one —(C₁₋₃ haloalkyl).
 39. The compound ofclaim 31, wherein R⁶ is a piperidinyl substituted with one —(C₁₋₃haloalkyl).
 40. The compound of claim 24, wherein R⁶ is either a—CH₂piperidinyl or a —CH₂pyrrolidinyl optionally substituted with 1-2R³⁶.
 41. The compound of claim 25, wherein R⁶ is either a—CH₂piperidinyl or a —CH₂pyrrolidinyl optionally substituted with 1-2R³⁶.
 42. The compound of claim 26, wherein R⁶ is either a—CH₂piperidinyl or a —CH₂pyrrolidinyl optionally substituted with 1-2R³⁶.
 43. The compound of claim 27, wherein R⁶ is either a—CH₂piperidinyl or a —CH₂pyrrolidinyl optionally substituted with 1-2R³⁶.
 44. The compound of claim 40, wherein R⁶ is a —CH₂piperidinylsubstituted with one —(C₁₋₅ alkyl).
 45. The compound of claim 41,wherein R⁶ is a —CH₂piperidinyl substituted with one —(C₁₋₅ alkyl). 46.The compound of claim 42, wherein R⁶ is a —CH₂piperidinyl substitutedwith one —(C₁₋₅ alkyl).
 47. The compound of claim 43, wherein R⁶ is a—CH₂piperidinyl substituted with one —(C₁₋₅ alkyl).
 48. The compound ofclaim 40, wherein R⁶ is a —CH₂piperidinyl substituted with one —(C₁₋₃haloalkyl).
 49. The compound of claim 41, wherein R⁶ is a—CH₂piperidinyl substituted with one —(C₁₋₃ haloalkyl).
 50. The compoundof claim 42, wherein R⁶ is a —CH₂piperidinyl substituted with one —(C₁₋₃haloalkyl).
 51. The compound of claim 43, wherein R⁶ is a—CH₂piperidinyl substituted with one —(C₁₋₃ haloalkyl).
 52. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide[1];N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexanecarboxamide[2];4,4-Difluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[3];trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[6];cis-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[7];trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide[8];cis-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide[9];trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[10];cis-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[11];trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide[12];cis-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide[13];trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide [14];cis-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide [15];N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[16];1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[17];1-Ethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[18];1-Isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[19];1-Cyclopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[20];1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[21];N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylazetidine-3-carboxamide[22];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)azetidine-3-carboxamide[23];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)azetidine-3-carboxamide[24];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[25];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)azetidine-3-carboxamide[26];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[27];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[28];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)azetidine-3-carboxamide[29];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)azetidine-3-carboxamide[30];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)azetidine-3-carboxamide[31];1-(2-methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[32];1-(2-isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[33];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[34];3-fluoro-1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[35];1-ethyl-3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[36];3-fluoro-1-isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[37];1-cyclopropyl-3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[38];3-fluoro-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[39];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylazetidine-3-carboxamide[40];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)azetidine-3-carboxamide[41];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)azetidine-3-carboxamide [42];3-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[43];1-(2,2-difluoroethyl)-3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[44];3-fluoro-1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[45];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)azetidine-3-carboxamide[46];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)azetidine-3-carboxamide[47];3-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)azetidine-3-carboxamide[48];3-fluoro-1-(2-methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[49];3-fluoro-1-(2-isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[50];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[51];1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[52];1-ethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[53];1-isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[54];1-cyclopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[55];1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[56];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpyrrolidine-3-carboxamide[57];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)pyrrolidine-3-carboxamide[58];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)pyrrolidine-3-carboxamide[59];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[60];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamide[61];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[62];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[63];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)pyrrolidine-3-carboxamide[64];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)pyrrolidine-3-carboxamide[65];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)pyrrolidine-3-carboxamide[66];1-(2-methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[67];1-(2-isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[68];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[69];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[70];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[71];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[72];1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[73];1-ethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[74];1-isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[75];1-cyclopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[76];1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[77];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[78];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)piperidine-4-carboxamide[79];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide[80];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[81];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[82];1-(2,2-difluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[83];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[84];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[85];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[86];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[87];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)piperidine-4-carboxamide[88];1-(2-methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[89];1-(2-isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[90];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[91];4-fluoro-1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[92];1-ethyl-4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[93];4-fluoro-1-isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[94];1-cyclopropyl-4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[95];4-fluoro-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[96];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[97];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)piperidine-4-carboxamide[98];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [99]; and4-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[100]; or a pharmaceutically acceptable salt thereof.
 53. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[101];1-(2,2-difluoropropyl)-4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[102];1-(2,2-difluoroethyl)-4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[103];4-fluoro-1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[104];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[105];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[106];4-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)piperidine-4-carboxamide[107];4-fluoro-1-(2-methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[108];4-fluoro-1-(2-isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[109];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[110];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[111];(S)-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[112];(R)-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[113];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[115];2-(4-fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[116];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[117];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[118];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide[119];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexanecarboxamide[120];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-1-carboxamide[121];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-methoxycyclohexane-1-carboxamide[122];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-methoxycyclohexane-1-carboxamide[123];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[124];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[125];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide[126];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide[127];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-1-yl)methyl)cyclohexane-1-carboxamide [128];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-1-yl)methyl)cyclohexane-1-carboxamide [129];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide[130];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide[131];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide [132];cis-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide [133];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[134];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-methylazetidine-3-carboxamide[135];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-ethylazetidine-3-carboxamide[136];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isopropylazetidine-3-carboxamide[137];1-cyclopropyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[138];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isobutylazetidine-3-carboxamide[139];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-neopentylazetidine-3-carboxamide[140];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)azetidine-3-carboxamide[141];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)azetidine-3-carboxamide [142];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)azetidine-3-carboxamide[143];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)azetidine-3-carboxamide[144];1-(2,2-difluoroethyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[145];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoro-2-methylpropyl)azetidine-3-carboxamide[146];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)azetidine-3-carboxamide[147];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)azetidine-3-carboxamide[148];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)azetidine-3-carboxamide[149];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-methoxyethyl)azetidine-3-carboxamide[150];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-isopropoxyethyl)azetidine-3-carboxamide[151];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3-carboxamide[152];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-methylazetidine-3-carboxamide[153];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-ethyl-3-fluoroazetidine-3-carboxamide[154];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-isopropylazetidine-3-carboxamide[155];1-cyclopropyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3-carboxamide[156];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-isobutylazetidine-3-carboxamide[157];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-neopentylazetidine-3-carboxamide[158];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-((1-methylcyclopropyl)methyl)azetidine-3-carboxamide [159];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-((1-(trifluoromethyl)cyclopropyl)methyl)azetidine-3-carboxamide [160];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(2-fluoroethyl)azetidine-3-carboxamide[161];1-(2,2-difluoroethyl)-N-(6-(1,2-dimethyl-H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3-carboxamide[162];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(2-fluoro-2-methylpropyl)azetidine-3-carboxamide[163];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(oxetan-3-yl)azetidine-3-carboxamide[164];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-((3-methyloxetan-3-yl)methyl)azetidine-3-carboxamide [165];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(oxetan-2-ylmethyl)azetidine-3-carboxamide[166];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(2-methoxyethyl)azetidine-3-carboxamide[167];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-1-(2-isopropoxyethyl)azetidine-3-carboxamide[168];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[169];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-methylpyrrolidine-3-carboxamide[170];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-ethylpyrrolidine-3-carboxamide[171];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isopropylpyrrolidine-3-carboxamide[172];1-cyclopropyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[173];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isobutylpyrrolidine-3-carboxamide[174];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-neopentylpyrrolidine-3-carboxamide[175];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)pyrrolidine-3-carboxamide[176];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)pyrrolidine-3-carboxamide [177];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)pyrrolidine-3-carboxamide[178];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamide[179];1-(2,2-difluoroethyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[180];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoro-2-methylpropyl)pyrrolidine-3-carboxamide[181];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)pyrrolidine-3-carboxamide[182];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)pyrrolidine-3-carboxamide[183];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)pyrrolidine-3-carboxamide[184];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxamide[185];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-isopropoxyethyl)pyrrolidine-3-carboxamide[186];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[187];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[188];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[189];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[190];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-ethylpiperidine-4-carboxamide[191];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isopropylpiperidine-4-carboxamide[192];1-cyclopropyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[193];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide[194];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[195];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-methylcyclopropyl)methyl)piperidine-4-carboxamide[196];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [197];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide[198];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[199]; and1-(2,2-difluoropropyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[200]; or a pharmaceutically acceptable salt thereof.
 54. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of: 1-(2,2-difluoroethyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[201];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoro-2-methylpropyl)piperidine-4-carboxamide[202];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[203];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[204];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-2-ylmethyl)piperidine-4-carboxamide[205];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-methoxyethyl)piperidine-4-carboxamide[206];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-isopropoxyethyl)piperidine-4-carboxamide[207];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-4-carboxamide[208];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-methylpiperidine-4-carboxamide[209];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-ethyl-4-fluoropiperidine-4-carboxamide[210];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-isopropylpiperidine-4-carboxamide[211];1-cyclopropyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-4-carboxamide[212];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide[213];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-neopentylpiperidine-4-carboxamide[214];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-((1-methylcyclopropyl)methyl)piperidine-4-carboxamide [215];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [216];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(2-fluoroethyl)piperidine-4-carboxamide[217];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[218];1-(2,2-difluoropropyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-4-carboxamide[219];1-(2,2-difluoroethyl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-4-carboxamide[220];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(2-fluoro-2-methylpropyl)piperidine-4-carboxamide[221];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxamide[222];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide [223];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(oxetan-2-ylmethyl)piperidine-4-carboxamide[224];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(2-methoxyethyl)piperidine-4-carboxamide[225];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-1-(2-isopropoxyethyl)piperidine-4-carboxamide[226];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[227];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[228];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide[229];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[230];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide[231];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)cyclohexanecarboxamide[232];4,4-difluoro-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[233];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[234];1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[235];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[236];1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[237];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide[238];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamide[239];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[240];1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[241];1-ethyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[242];1-isopropyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[243];1-cyclopropyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[244];1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[245];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[246];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[247];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[248];1-(2,2-difluoropropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[249];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[250];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[251];4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[252];4-fluoro-1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[253];4-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[254];4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[255];1-(2,2-difluoropropyl)-4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[256];1-(2,2-difluoroethyl)-4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[257];4-fluoro-1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[258];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[259];2-(4-fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)acetamide[260];N-(6-(1-methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[261];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[262];4,4-difluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[263];1-methyl-N-(6-(1-methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[264];N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide[265];N-(6-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide[266];3,3-difluoro-N-(6-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[267];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3,3-difluorocyclobutane-1-carboxamide[268];2,2,3,3-tetramethyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[269];N-(6-(1-methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[270];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[271];2-(4-isobutylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[272];2-(3,3-dimethylazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[273];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[274];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[275];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[276];2,2,3,3-tetramethyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[277];N-(6-(4-methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[278];N-(6-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[279];4-fluoro-1-isobutyl-N-(6-(4-methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[280];4-fluoro-1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[281];1-ethyl-4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[282];4,4-difluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [283];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[284];N-(6-(1-ethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[285];N-(6-(1-cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[286];2-(pyrrolidin-1-yl)-N-(6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[287];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[288];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[289];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[290];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[291];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[292];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[293];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[294];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[295];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[296];N-(6-(1-cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[297];N-(6-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-1-carboxamide[298];4,4-difluoro-N-(6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[299]; and4,4-difluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[300]; or a pharmaceutically acceptable salt thereof.
 55. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:7-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[301];2-(cyclobutyl(methyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[302];2-(diethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[303];N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[304];N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[305];N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[306];N-(6-(3-methylisoxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[307];N-(6-(oxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[308];4-fluoro-1-isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[309];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide[310];(S)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[311];2-fluoro-2-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)propanamide[312];(R)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[313];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[314];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d4)acetamide[315];4-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide[316];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[317];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[318];2-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[319];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[320];2-fluoro-2-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)propanamide[321];1-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[322];3,3-difluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[323];2-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[324];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[325];2-(2-fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[326];trans-4-(dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[327];1-benzoyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[328];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[330];1′-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[331];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[332];trans-4-(hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[333]; methyl2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[334];1-benzyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[335];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[336];1-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[337];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide[338];trans-4-formyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[339];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-2-carboxamide[340];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[341];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[342];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[343];2-((2R,6S)-2,6-dimethylmorpholino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[344];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[345];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[346];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[347];(S)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide[348];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[349];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[350];2-(4-ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[351];2-(4-isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[352];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[353];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[354];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[355];7-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[356];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[357];1-(2-hydroxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[358];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[359];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[360];2-(3,3-dimethylazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[361];(R)—N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-carboxamide[362];(R)-1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[363];N-(4-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide[364];trans-4-amino-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[365];N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[366];N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide[367];N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide[368];N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[369];N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide[370];N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide[371];N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[372];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-fluoro-2-methylpropanamide[373];2-(diethylamino)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[374];2-(cyclobutyl(methyl)amino)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[375];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-fluorocyclopropane-1-carboxamide[376];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-methyl-2-azaspiro[3.3]heptane-6-carboxamide[377];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-fluoroethyl)-2-azaspiro[3.3]heptane-6-carboxamide[378];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[379];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-7-methyl-7-azaspiro[3.5]nonane-2-carboxamide[380];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-fluorocyclohexane-1-carboxamide[381];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(dimethylamino)cyclohexane-1-carboxamide[382];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-formylcyclohexane-1-carboxamide[383];trans-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(hydroxymethyl)cyclohexane-1-carboxamide[384];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[385];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[386];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-hydroxyethyl)piperidine-4-carboxamide[387]; methyl2-(4-((6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[388];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoropropyl)piperidine-4-carboxamide[389];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-fluoropropyl)piperidine-4-carboxamide[390];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[391];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[392];1-benzoyl-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[393];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1′-methyl-[1,4′-bipiperidine]-4-carboxamide[394];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[395];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[396];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[397];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[398];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide[399]; and(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide[400]; or a pharmaceutically acceptable salt thereof.
 56. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-methylpiperazine-1-carboxamide[401];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3,3-dimethylazetidin-1-yl)acetamide[402];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[403];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-1-yl)acetamide[404];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-1-yl)acetamide[405];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[406];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[407];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[408];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[409];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[410];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[411];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[412];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[413];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[414];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-ethylpiperazin-1-yl)acetamide[415];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-(2-fluoroethyl)piperazin-1-yl)acetamide[416];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2,4-dimethylpiperazin-1-yl)acetamide[417];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-isopropylpiperazin-1-yl)acetamide[418];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[419];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide[420];(R)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[421];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[422];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[423];(S)—N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinopropanamide[424];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[425];N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[426];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[427];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[428];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[429];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[430];2-(diethylamino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[431];2-(cyclobutyl(methyl)amino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[432];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide[433];1-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[434];3,3-difluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[435];2-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[436];2-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[437];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[438];7-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[439];1-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[440];4,4-difluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[441];trans-4-methoxy-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[442];trans-4-(dimethylamino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[443];trans-4-formyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[444];trans-4-(hydroxymethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[445];trans-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[446];trans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [447];trans-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide[448];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[449];(R)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[450];(R)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[451];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[452];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[453];1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[454];4-fluoro-1-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[455];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[456];4-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[457];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[458];1-(2-hydroxyethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[459];1-(2-methoxyethyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[460]; methyl2-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[461];1-isopropyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[462];1-cyclopropyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[463];(R)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[464];(S)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[465];1-(2,2-difluoropropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[466];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[467];1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[468];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[469];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [470];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[471];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[472];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[473];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[474];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[475];1-benzoyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[476];1′-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[477];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[478];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[479];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[480];(R)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[481];1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[482];(R)-1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[483];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[484];4-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide[485];2-(3,3-dimethylazetidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[486];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[487];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[488];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[489];(R)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[490];(S)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[491];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[492];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[493];2-(4-fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[494];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[495];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[496];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[497];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[498];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[499]; andN-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[500]; or a pharmaceutically acceptable salt thereof.
 57. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:2-(4-ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[501];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[502];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[503];2-(4-isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[504];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[505];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide[506];(R)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[507];(S)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[508];(S)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[509];(S)—N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide[510];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[511];N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[512];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[513];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[514];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[515];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide[516];2-fluoro-2-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)propanamide[517];2-(diethylamino)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[518];2-(cyclobutyl(methyl)amino)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[519];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide[520];1-fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[521];3,3-difluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[522];2-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[523];2-(2-fluoroethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[524];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[525];7-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[526];1-fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[527];trans-4-methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[528];trans-4-(dimethylamino)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[529];trans-4-formyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[530];trans-4-(hydroxymethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[531];trans-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[532];trans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[533];trans-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide[534];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[535];(R)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[536];(R)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[537];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[538];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[539];1-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[540];4-fluoro-1-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[541];1-ethyl-4-fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[542];1-(2-fluoroethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[543];4-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[544];1-(2,2-difluoroethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[545];1-(2-hydroxyethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[546];1-(2-methoxyethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[547]; methyl2-(4-((6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[548];1-isopropyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[549];1-cyclopropyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[550];(R)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[551];(S)-1-(2-fluoropropyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[552];1-(2,2-difluoropropyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[553];1-isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[554];4-fluoro-1-isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[555];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[556];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [557];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[558];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[559];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[560];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[561];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[562];1-benzoyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[563];1′-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[564];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[565];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[566];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[567];(S)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[568];1-isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[569];(R)-1-isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[570];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[571];4-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperazine-1-carboxamide[572];2-(3,3-dimethylazetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[573];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[574];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[575];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[576];(R)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[577];(S)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[578];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[579];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[580];2-(4-fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[581];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[582];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[583];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[584];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[585];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[586];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[587];2-(4-ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[588];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[589];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[590];2-(4-isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[591];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[592];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide[593];(R)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[594];(S)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[595];(S)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[596];(S)—N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinopropanamide[597];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[598];N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[599]; and2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[600]; or a pharmaceutically acceptable salt thereof.
 58. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide [601];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide [602];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[603];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro-2-methylpropanamide[604]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(diethylamino)acetamide[605];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(cyclobutyl(methyl)amino)acetamide[606]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide[607];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-fluorocyclopropane-1-carboxamide[608];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-3,3-difluorocyclobutane-1-carboxamide[609];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-methyl-2-azaspiro[3.3]heptane-6-carboxamide[610];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-fluoroethyl)-2-azaspiro[3.3]heptane-6-carboxamide[611];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[612];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-7-methyl-7-azaspiro[3.5]nonane-2-carboxamide[613];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-fluorocyclohexane-1-carboxamide[614];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-1-carboxamide[615];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(dimethylamino)cyclohexane-1-carboxamide[617];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-formylcyclohexane-1-carboxamide[618];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(hydroxymethyl)cyclohexane-1-carboxamide[619];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[620];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-1-yl)methyl)cyclohexane-1-carboxamide[621];trans-N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide[622]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[623];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[624];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[625]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[626]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[627];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[628];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-1-methylpiperidine-4-carboxamide[629];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-ethyl-4-fluoropiperidine-4-carboxamide[630];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl)piperidine-4-carboxamide[631];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-1-(2-fluoroethyl)piperidine-4-carboxamide[632];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2,2-difluoroethyl)piperidine-4-carboxamide[633];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-hydroxyethyl)piperidine-4-carboxamide[634];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-methoxyethyl)piperidine-4-carboxamide[635]; methyl2-(4-((6-(1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[636];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isopropylpiperidine-4-carboxamide[637];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-cyclopropylpiperidine-4-carboxamide[638];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoropropyl)piperidine-4-carboxamide[639];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoropropyl)piperidine-4-carboxamide[640];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2,2-difluoropropyl)piperidine-4-carboxamide[641];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[642];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide[643];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide[644];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoro-2-methylpropyl)piperidine-4-carboxamide[645];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide[646];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[647];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[648];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[649];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[650];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[651];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-benzoylpiperidine-4-carboxamide[652];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1′-methyl-[1,4′-bipiperidine]-4-carboxamide[653];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[654];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[655];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[656];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[657];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide[658];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide[659];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-4-methylpiperazine-1-carboxamide[661];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3,3-dimethylazetidin-1-yl)acetamide[662];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[663];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-1-yl)acetamide[664];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-1-yl)acetamide[665];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[666];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[667];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[668];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)acetamide[669];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[670];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide[671];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[672];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(difluoromethyl)piperidin-1-yl)acetamide[673];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[674];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[675];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[676];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[677];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-ethylpiperazin-1-yl)acetamide[678];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(2-fluoroethyl)piperazin-1-yl)acetamide[679];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,4-dimethylpiperazin-1-yl)acetamide[680];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-isopropylpiperazin-1-yl)acetamide[681];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide[682]; N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide[683];(R)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[684];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[685];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[686];(S)—N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide[687];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[688];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[689];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-azabicyclo[2.2.1]heptan-7-yl)acetamide[690];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetamide[691];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetamide[692];N-(6-(1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)acetamide[693]; 2-fluoro-2-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide[694]; 2-(diethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[695];2-(cyclobutyl(methyl)amino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[696]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide[697];1-fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[698];3,3-difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[699]; and2-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[700]; or a pharmaceutically acceptable salt thereof.
 59. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:2-(2-fluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[701];N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[702];7-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[703];1-fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[704];4,4-difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[705];trans-4-methoxy-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[706];trans-4-(dimethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[707];trans-4-formyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[708];trans-4-(hydroxymethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[709];trans-4-morpholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[710];trans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[711];trans-4-((4-methylpiperazin-1-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[712]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide[713]; (R)—N-(6-(thiazol-5-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[714];(R)—N-(6-(thiazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[715]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[716]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[717];1-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[718];4-fluoro-1-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[719];1-ethyl-4-fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[720];1-(2-fluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[721];4-fluoro-1-(2-fluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[722];1-(2,2-difluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[723];1-(2-hydroxyethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[724];1-(2-methoxyethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[725]; methyl2-(4-((6-(thiazol-5-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[726];1-isopropyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[727];1-cyclopropyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[728];(R)-1-(2-fluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[729];(S)-1-(2-fluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[730];1-(2,2-difluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[731];N-(6-(thiazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[732];1-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[733];4-fluoro-1-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[734];1-(2-fluoro-2-methylpropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[735];N-(6-(thiazol-5-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide[736];1-(oxetan-3-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[737];1-((3-methyloxetan-3-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[738];1-neopentyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[739];1-(methylsulfonyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[740];1-(2-(pyrrolidin-1-yl)acetyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[741];1-benzoyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[742];1′-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[743];1-(tetrahydro-2H-pyran-4-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[744];1-(oxazol-2-ylmethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[745];1-(pyridin-2-ylmethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[746]; (S)—N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[747];1-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[748];(R)-1-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[749];N-(6-(thiazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[750];4-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperazine-1-carboxamide[751];2-(3,3-dimethylazetidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[752]; 2-(pyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[753];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[754];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[755];(R)-2-(2-methylpyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[756];(S)-2-(2-methylpyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[757];2-(pyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide[758];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[759]; 2-(piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[760];2-(4-fluoropiperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[761];2-(4-methylpiperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[762];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[763];N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide[764];2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[765];2-(piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide[766];2-(4-methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[767];2-(4-ethylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[768];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[769];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[770];2-(4-isopropylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[771];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[772]; 2-morpholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [773];(R)-2-(3-methylmorpholino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[774];(S)-2-(3-methylmorpholino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[775];(S)-2-(2-methylmorpholino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[776]; (S)-2-morpholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide[777]; 2-(morpholin-2-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[778];2-(4-methylmorpholin-2-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[779];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[780];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[781];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[782];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide[783];2-fluoro-2-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)propanamide [784];2-(diethylamino)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[785];2-(cyclobutyl(methyl)amino)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [786];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide[787];1-fluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[788];3,3-difluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[789];2-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide [790];2-(2-fluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[791];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[792];7-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide [793];1-fluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[794];trans-4-methoxy-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[795];trans-4-(dimethylamino)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [796];trans-4-formyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[797];trans-4-(hydroxymethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [798];trans-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[799]; andtrans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [800]; or a pharmaceuticallyacceptable salt thereof.
 60. The compound of claim 1, wherein thecompound of Formula I is selected from the group consisting of:trans-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide[801];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide[802];(R)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[803];(R)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[804];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[805];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[806];1-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[807];4-fluoro-1-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[808];1-ethyl-4-fluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[809];1-(2-fluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[810];4-fluoro-1-(2-fluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [811];1-(2,2-difluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [812];1-(2-hydroxyethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [813];1-(2-methoxyethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [814]; methyl2-(4-((6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate [815];1-isopropyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[816];1-cyclopropyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[817];(R)-1-(2-fluoropropyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-yl)isoquinolin-3-yl)piperidine-4-carboxamide [818];(S)-1-(2-fluoropropyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-yl)isoquinolin-3-yl)piperidine-4-carboxamide [819];1-(2,2-difluoropropyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [820];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[821];1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[822];4-fluoro-1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [823];1-(2-fluoro-2-methylpropyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [824];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [825];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[826];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide [827];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[828];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[829];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide [830];1-benzoyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[831];1′-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[832];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide [833];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide [834];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide [835];(R)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[836];1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[837];(R)-1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide[838];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[839];4-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide[840];2-(3,3-dimethylazetidin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [841];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[842];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[843];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[844];(R)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[845];(S)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[846];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide [847];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[848];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[849];2-(4-fluoropiperidin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [850];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide [851];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [852];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide [853];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide [854];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide [855];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide [856];2-(4-ethylpiperazin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [857];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [858];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[859];2-(4-isopropylpiperazin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [860];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[861];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide[862];(R)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide [863];(S)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide [864];(S)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[865];(S)—N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide[866];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[867];N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide [868];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[869];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[870];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[871];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide [872];2-fluoro-2-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)propanamide[873];2-(diethylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[874];2-(cyclobutyl(methyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[875];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide[876];1-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide[877];3,3-difluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[878];2-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[879];2-(2-fluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide[880];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide[881];7-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide[882];1-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[883];4,4-difluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[884];trans-4-methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[885];trans-4-(dimethylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[886];trans-4-formyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[887];trans-4-(hydroxymethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[888];trans-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[889];trans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide [890];trans-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide [891];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)azetidine-3-carboxamide[892];(R)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[893];(R)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[894];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[895];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[896];1-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[897];4-fluoro-1-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[898];1-ethyl-4-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[899]; and1-(2-fluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[900]; or a pharmaceutically acceptable salt thereof.
 61. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:4-fluoro-1-(2-fluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[901];1-(2,2-difluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[902];1-(2-hydroxyethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[903];1-(2-methoxyethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[904]; methyl2-(4-((6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[905];1-isopropyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[906];1-cyclopropyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[907];(R)-1-(2-fluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[908];(S)-1-(2-fluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[909];1-(2,2-difluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[910];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide[911];1-isobutyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[912];4-fluoro-1-isobutyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[913];1-(2-fluoro-2-methylpropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[914];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [915];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide[916];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide[917];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide[918];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(methylsulfonyl)piperidine-4-carboxamide[919];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[920];1-benzoyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[921];1′-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[922];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide[923];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl)piperidine-4-carboxamide[924];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl)piperidine-4-carboxamide[925];(S)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-3-carboxamide[926];1-isobutyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-3-carboxamide[927];(R)-1-isobutyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-3-carboxamide[928];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[929];4-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperazine-1-carboxamide[930];2-(3,3-dimethylazetidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[931];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[932];(S)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[933];(R)-2-(3-fluoropyrrolidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[934];(R)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[935];(S)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide[936];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[937];2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [938];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[939];2-(4-fluoropiperidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[940];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide[941];2-(4-(difluoromethyl)piperidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [942];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-1-yl)acetamide [943];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide[944];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)propanamide[945];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[946];2-(4-ethylpiperazin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[947];2-(4-(2-fluoroethyl)piperazin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [948];(S)-2-(2,4-dimethylpiperazin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [949];2-(4-isopropylpiperazin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[950];2-(4-cyclopropylpiperazin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[951];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide[952];(R)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[953];(S)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide[954];(S)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide[955];(S)—N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinopropanamide[956];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(morpholin-2-yl)acetamide[957];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide[958];2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [959];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [960];2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [961];2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [962];N-(8-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide[963];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(phenylsulfonyl)piperidine-4-carboxamide[964];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d3)piperazin-1-yl)acetamide[965];N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[966];1-ethyl-N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[967];N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[968];N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexanecarboxamide[969];N-(6-(isothiazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[970];(S)—N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[971];1-isobutyl-N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[972]; N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide [973];(R)—N-(6-(oxazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide[974]; (R)—N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide[975];N-(6-(oxazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[976];N-(6-(oxazol-5-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide[977];1′-methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide[978];cis-4-morpholino-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[979];2-(cyclobutyl(methyl)amino)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide[980]; N-(6-(oxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[981];(R)-2-(2-methylpyrrolidin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide[982];2-(4-methylpiperazin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide[983];N-(6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide[984];N-(6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[985];3,3-difluoro-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide[986];(R)—N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide[987];(R)—N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-3-carboxamide[988];1-methyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[989];N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [990];1-benzoyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[991];N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[993];N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide[994];2-(4-methylpiperazin-1-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide[995];2-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide [996];N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [997];N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide[998];N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide[999]; and2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide[1000]; or a pharmaceutically acceptable salt thereof.
 62. The compoundof claim 1, wherein the compound of Formula I is selected from the groupconsisting of:cis-4-methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1001];(R)—N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide[1002];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrimidin-2-ylmethyl)piperidine-4-carboxamide[1003];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrazin-2-ylmethyl)piperidine-4-carboxamide[1004];1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [1005];1-(2-hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1006];trans-4-((4-methylpiperazin-1-yl)methyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1007];2-isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide[1008];3-isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)propanamide[1009]; tert-butyl2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetate[1010];2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)aceticacid [1011];2-(4-methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[1012];N-(7-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1013];N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[1014];N-(7-fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[1015];N-(8-fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[1016];trans-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1017];trans-4-((3-fluoroazetidin-1-yl)methyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1018];N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[1019];1-isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1020];4-fluoro-1-isobutyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1021];N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1022];4-fluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide[1023];N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[1024]; tert-butyl(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamate [1025];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)but-2-ynamide [1026];N-(7-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[1027];N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[1028];2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide[1029];(R)-2-(2-methylpyrrolidin-1-yl)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide[1030];2-(cyclobutyl(methyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide[1031];trans-4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylicacid [1032];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide-2,2-d2[1033];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinopropanamide[1034];trans-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide[1035];1-(1-isobutylpiperidin-4-yl)-3-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)urea[1036];1-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea[1037];1-isobutyl-N-(6-(4-methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1038];1-isobutyl-N-(6-(1-methyl-1H-tetrazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1039];N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1040];1-methyl-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1041];N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide[1042];N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[1043];N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide[1044];N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[1045];N-(6-(2-(diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide[1046];N-(6-(2-(diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide[1047];N-(6-(2-(diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide[1048];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(1,4-oxazepan-4-yl)acetamide[1049];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide-2,2-d2[1050];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide-2,2-d2[1051];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(morpholino-d8)acetamide[1052];N-(7-fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide[1053];N-(6-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1054];N-(6-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[1055];N-(6-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide[1056];1-(2,2-difluoropropyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1057];1-((3-methyloxetan-3-yl)methyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1058];4-methyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperazine-1-carboxamide[1059];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)cyclobutane-1-carboxamide[1060];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide[1061];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(morpholinomethyl)bicyclo[1.1.1]pentane-1-carboxamide[1062];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)bicycle[1.1.1]pentane-1-carboxamide [1063];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide[1064];trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide[1065];(S)—N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide[1066];N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide[1067];N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinopropanamide[1068];N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)propanamide[1069];1-(2-hydroxy-2-methylpropyl)-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1070];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide[1071];1-(2-hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1072];N-(6-(2H-1,2,3-triazol-2-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide[1073];N-(6-(1H-1,2,3-triazol-1-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide[1074];N-(6-(5-(Dimethylamino)-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1075];N-(6-(5-(Dimethylamino)-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide[1076];2-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[1077];2-(4-Hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide[1078];1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide[1079];1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide[1080];cis-4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1081];cis-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide[1082];3-(hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide[1083]; methyltrans-4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylate[1084];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide[1085];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(methyl-d₃)propyl-1,1,2,3,3,3-d₆)piperidine-4-carboxamide[1086];1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide[1087];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide [1088];N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide-2,2-d₂[1089];1-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(1-methylpiperidin-4-yl)urea[1090];trans-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide [1091]; and1-isobutyl-N-(6-(1-methyl-1H-tetrazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide[1092];N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(pyrrolidin-1-yl)acetamide[1093]; or a pharmaceutically acceptable salt thereof.
 63. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.
 64. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 11, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 65. A method of treating adisorder or disease in a patient, wherein the disorder or disease isselected from the group consisting of: chronic inflammation, diabetes,cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF),degenerative disc disease, bone/osteoporotic fractures, a bone orcartilage disease, a neurological disorder, osteoarthritis, lungdisease, a fibrotic disorder, the method comprising administering to thepatient a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, or a pharmaceutical composition. 66.A method of claim 65, wherein the disorder or disease is cancer.
 67. Amethod of claim 65, wherein the disorder or disease is pulmonaryfibrosis.
 68. A method of claim 65, wherein the disorder or disease isidiopathic pulmonary fibrosis (IPF).
 69. The method of claim 65, whereinthe disorder or disease is lung disease.
 70. A method of claim 65,wherein the disorder or disease is degenerative disc disease.
 71. Amethod of claim 65, wherein the disorder or disease is abone/osteoporotic fracture.
 72. A method of claim 65, wherein thedisorder or disease is a bone or cartilage disease.
 73. A method ofclaim 65, wherein the disorder or disease is osteoarthritis.
 74. Amethod of claim 65, wherein the disorder or disease is a neurologicaldisorder.
 75. The method of claim 66, wherein the cancer is selectedfrom the group consisting of: osteoma, hemangioma, granuloma, xanthoma,osteitis deformans, meningioma, meningiosarcoma, and gliomatosis,astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma multiform, oligodendroglioma, oligodendrocytoma,schwannoma, retinoblastoma, and congenital tumors, neurofibroma,meningioma, glioma, and sarcoma.
 76. The method of claim 74, wherein thedisorder or disease is a neurological disorder, wherein the neurologicalcondition/disorder/disease is selected from the group consisting of:frontotemporal dementias, dementia with lewy bodies, prion diseases,multiple system atrophy, inclusion body myositis, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, and Charcot-Marie-Tooth disease.77. The method of claim 74, wherein the disorder or disease is selectedfrom the group consisting of: Alzheimer's disease, amyotrophic lateralsclerosis (ALS), down syndrome, frontotemporal dementia (FTD) includingFTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporaldementia (bvFTD), FTD in patients with motor neuron disease (MND)(typically amyotrophic lateral sclerosis, also called FTD-ALS),corticobasal degeneration (CBD) (also called corticobasal ganglionicdegeneration), progressive supranuclear palsy, primary progressiveaphasia (PPA), Prion Diseases, globular glial tauopathy (GGT), myotonicdystrophy type 1 (DM1) (also called Steinert disease), myotonicdystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guamcomplex, argyrophilic grain disease, dementia pugilistica,post-encephalitic parkinsonism, lewy body dementia, Parkinson's disease,Pick's disease, and additional diseases with pronouncedneurodegeneration such as autism, dementia, epilepsy, Huntington'sdisease, multiple sclerosis; diseases and disorders associated withacquired brain injury such as chronic traumatic encephalopathy,traumatic brain injury, tumor, and stroke.
 78. A method of claim 77,wherein the disorder or disease is Alzheimer's disease.
 79. The methodof claim 74, wherein the disorder or disease is a neurological disorderassociated with tau protein, amyloid, alpha-synuclein, Tar DNA-bindingProtein of 43 KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS)pathology.
 80. The method of claim 65, wherein the disorder or diseaseis a fibrotic disorder, wherein the fibrotic disorder is selected fromthe group consisting of: skin fibrosis; scleroderma; progressivesystemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis;glomerulosclerosis; glomerulonephritis; hypertrophic scar formation;uterine fibrosis; renal fibrosis; cirrhosis of the liver, liverfibrosis; adhesions; chronic obstructive pulmonary disease; fibrosisfollowing myocardial infarction; pulmonary fibrosis; fibrosis andscarring associated with diffuse/interstitial lung disease; centralnervous system fibrosis; fibrosis associated with proliferativevitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease,and radiation fibrosis.
 81. The method of claim 65, wherein the patientis a human.
 82. The method of claim 65, wherein the compound inhibitsone or more proteins in the Wnt pathway.
 83. The method of claim 65,wherein the compound inhibits signaling induced by one or more Wntproteins.
 84. The method of claim 65, wherein the compound inhibitsDYRK1A.
 85. The method of claim 65, wherein the compound inhibits GSK3β.86. The method of claim 65, wherein the compound inhibits DYRK1A andGSK3β.
 87. The method of claim 65, wherein the compound inhibits akinase activity.
 88. A method of preventing or reducing angiogenesis ina patient, the method comprising administering to the patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, or a pharmaceutical composition.